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Down syndrome: Neurobiological alterations and therapeutic targets
Accepted Manuscript Title: Down syndrome: neurobiological alterations and therapeutic targets Authors: Rosa Anna Vacca, Sweta Bawari, Daniela Valenti, Devesh Tewari, Seyed Fazel Nabavi, Samira Shirooie, Archana N. Sah, Mariateresa Volpicella, Nady Braidy, Seyed Mohammad Nabavi PII: DOI: Reference:
S0149-7634(18)30802-9 https://doi.org/10.1016/j.neubiorev.2019.01.001 NBR 3313
To appear in: Received date: Revised date: Accepted date:
17 October 2018 2 January 2019 2 January 2019
Please cite this article as: Vacca RA, Bawari S, Valenti D, Tewari D, Fazel Nabavi S, Shirooie S, Sah AN, Volpicella M, Braidy N, Nabavi SM, Down syndrome: neurobiological alterations and therapeutic targets, Neuroscience and Biobehavioral Reviews (2019), https://doi.org/10.1016/j.neubiorev.2019.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Down syndrome: neurobiological alterations and therapeutic targets
Rosa Anna Vacca1*, Sweta Bawari2, Daniela Valenti1, Devesh Tewari2, Seyed Fazel Nabavi3, Samira Shirooie4, Archana N. Sah2, Mariateresa Volpicella5, Nady Braidy6, Seyed Mohammad
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Nabavi3
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of
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Research, Bari, Italy;
Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Nainital,
India;
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran,
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Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Kermanshah University of
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Iran;
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Medical Sciences, Iran;
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy;
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Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Australia.
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*Correspondence at:
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Rosa Anna Vacca, Institute of Biomembranes, Bioenergetics and Molecular Biothecnology, IBIOM-CNR, Via Amendola 165/A, 70126 Bari, Italy;
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e-mail: [email protected]
Highlights Down syndrome is both a neurodevelopment and neurodegenerative disorder Genetic and metabolic alterations involved in Down syndrome neuropathology are discussed Drugs targeting altered genes and metabolic pathways for therapeutic challenge in DS are discussed 1
Abstract Down syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal
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loss, anomalous glutamatergic transmission and N-methyl-D-aspartate receptor signalling, mitochondrial dysfunction, increased oxidative stress and inflammation, differentially expressed
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microRNAs, increased expression of crucial chromosome 21 genes, and DNA hyper-methylation and hyperactive homocysteine trans-sulfuration pathway, are common incongruities that have been reported in DS and might contribute to cognitive impairment and intellectual disability. This review
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provides an update on metabolic and neurobiological alterations in DS. It also provides an overview
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of the currently available pharmacological therapies that may influence and/or reverse these
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alterations in DS.
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Key words: chromosome 21 trisomy; neurodevelopment disease; neurotransmission; neurogenesis; mitochondrial dysfunction; neurodegeneration
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Abbreviations:
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Aβ, beta-amyloid; AD, Alzheimer’s disease; AMPK, 5' AMP-activated protein kinase; APP, amyloid precursor protein; BAX, BCL2-Associated X Protein; CAT, catalase; CBS, cystathionine
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beta-synthase; CNS, central nervous system; CoQ10, Coenzyme Q10; Drp1, dynamin-related protein 1; DS, Down syndrome; DSCR, Down syndrome critical region; DYRK1A, dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A; EGCG, epigallocatechin-3-gallate; GABA, γaminobutyric acid; GIs, γ-secretase inhibitors; GPCR, G-protein coupled receptor; GPX, glutathione peroxidase; Hsa21, human chromosome 21; iPSCs, induced pluripotent stem cells; LTD, long-term depression; LTP, long-term potentiation; Mecp2, methyl-CpG binding protein 2; 2
miRNAs, microRNAs; Mnf2, mitofusin 2; MRC, mitochondrial respiratory chain; mTOR, mammalian target of rapamycin; NAM, negative allosteric modulator; NFAT, nuclear factor of activated T-cells; NKCC1, Na-K-Clcotransporter 1; NMDA, N-methyl-D- aspartate; NPCs, neural progenitor cells; NRIP1, nuclear receptor interacting protein 1; Opa1, optic atrophy 1; PKA, protein kinase; A; PiB, C-labeled Pittsburgh compound B; RCAN1, regulator of calcineurin 1; RIP140,
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receptor-interacting protein 140; ROS, reactive oxygen species; SOD, superoxide dismutase; TSP-
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1, thrombospondin 1.
Table of Contents 1. Introduction
Down syndrome
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2.1. Impairments in neurogenesis
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2. Alterations in metabolic and signalling pathways critical for the neuropathology of
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2.1.1. Genetic deregulation
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2.1.2. Epigenetic deregulation 2.1.3. Mitochondrial dysfunction 2.2. Impairments in neurotransmission
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2.1.1. GABAergic transmission
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2.1.2. Glutamatergic transmission 2.1.3. Other synaptic transmissions
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2.3. Impairments in neuroplasticity 2.3.1. Astrocyte-mediated synaptic dysfunction 2.4 Neurodegeneration
3. Selected pharmacological interventions and their targets in Down syndrome 3.1.
Bumetanide and Basmisanil RG1662
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Fluorexetine 3
3.3.
Memantine
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Donepezil and β- and γ-secretase modulators
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Coenzyme Q10, metformin and melatonin
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Naturally occurring phytochemicals
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Other dietary supplements
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4. Concluding remarks and future prospective 5. Acknowledgments
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6. References
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1. Introduction Down syndrome (DS) is a genetic disorder that develops as a consequence of an aneuploidy of human chromosome 21 (Hsa21) (Antonarakis et al., 2004; Letourneau et al., 2014; Opitz and Gilbert-Barness, 1990; Ruparelia et al., 2010). The most frequent form of DS is a result of full Hsa21 trisomy, which is an outcome of the inability of Hsa21 to segregate during meiosis in a
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developing ovum or, to a lesser extent, in sperm, culminating in an extra copy of the entire Hsa21 in all cell types. The mosaic form is rare and occurs in 3-4 % of DS population, in which some cells
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within a single tissue type exhibit a normal karyotype while others exhibit a Hsa21 trisomy (Antonarakis, 2017; Asim et al., 2015; Rachidi and Lopes, 2008; Reeves et al., 2001; Sherman et al., 2007). The occurrence of partial Hsa21 trisomy leading to DS phenotype is extremely rare
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(Pelleri et al., 2016).
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The incidence of DS is estimated to be 1/750-800 live new-borns, but the risk of Hsa21 non-
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disjunction increases with advanced maternal age (Loane et al., 2013; McKenzie et al., 2016;
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Rudolf et al., 2017). Differences in the use of prenatal screening and pregnancy termination have led to a wide variation in live birth prevalence between countries (Morice et al., 2008; Rudolf et al., 2017). A recent epidemiological study on the prevalence of major birth defects in the live birth
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population in the United States between 2004 and 2006 reported that the estimated annual number
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of infants born each year with DS was 5,657 (Kirby, 2017). In Europe, a twenty-year study (19902009) showed that the total number of cases of infants born with DS was about 14,000 or about 700
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per year (Loane et al., 2013). In comparison, approximately 21,000 infants are born with DS in India every year (Verma, 2000; Verma and Bijarnia, 2002). However, a prospective cohort-based study from an Indian tertiary health care centre between 2005 and 2010 reported a higher incidence of mortality (13 %, of which 80.3 % in children less than 2 years of age). These discrepancies may be due to poor family conditions and reporting errors from medical and allied healthcare professionals (Nahar et al., 2013). 5
While trisomy 21, as the genetic cause of DS, was first reported by Lejeune, Gautier and Turpin nearly 60 years ago (Lejeune et al., 1959), there has been a concerted effort to identify the pathogenic mechanism/s through which the trisomy 21 induces the clinical phenotype. Currently,
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the genotype/phenotype correlation in DS remains unclear.
DS is considered the most prominent condition associated with neurodevelopmental abnormalities
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which determine delay or failure in the acquisition of motor skills, speaking and reading with shortterm memory impairment and learning difficulties (for refs see the reviews (Roizen and Patterson, 2003; Sherman et al., 2007). The syndrome is characterized by neuropathological changes occurring
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in the foetal and neonatal life that lead to alterations in brain development. Indeed, the most striking
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hallmarks of DS phenotype are impairments of brain development and intellectual disability, as
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well as craniofacial defects (Kazemi et al., 2016). Additionally, the brains from people with DS
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have structural and functional abnormalities with developmental alterations in morphogenesis, such
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as reduction in brain volume (including cerebral grey and white matter and cerebellum), and histogenesis, including cortical dysgenesis, delayed myelination, lower neuronal density and abnormal synaptic plasticity (Rachidi and Lopes, 2011). Almost all DS population develop in adult
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life neuropathological features leading to early ageing, senile dementia and neurological alterations
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consistent with the Alzheimer’s disease (AD) phenotype, including extracellular plaques and intracellular tangles (Head et al., 2016; Zis and Strydom, 2018). For these reasons, DS is often
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considered a neurodegenerative disorder.
Apart from intellectual disabilities, a wide range of typical traits can be recognized in DS population that are associated with numerous comorbidities with a high phenotypic variation, but occurring with a higher frequency with respect to the euploid population. The most frequent DSassociated diseases are congenital cardiac defects, occurring in almost 50% of babies with DS 6
(Diamandopoulos and Green, 2018). This is followed by acute lymphoblastic leukaemia, occurring in children with DS that are aged less than 5 years old with a frequency of 1/300 and an incidence 40.7 times greater than that in individuals without DS at the same age (Chisholm, 2018). As well, gastro-intestinal diseases such as Hirschprung disease, affects about 2% of babies born with DS and constitutes about 12% of all cases of gastro-intestinal congenital malformations (Asim et al., 2015;
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Holmes, 2014). Other common medical conditions in DS population are otolaryngologic and periodontal diseases, visual impairments, obesity, obstructive sleep apnea, increased susceptibility
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to seizures, and respiratory diseases (Carfì et al., 2014; Pueschel, 1990; Roizen and Patterson, 2003). DS is also correlated with male infertility (Stefanidis et al., 2011). In addition, people with DS are highly vulnerable to auto-inflammatory diseases such as celiac disease, thyroiditis and
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alopecia indicative of a chronic deregulation of the immune system (Sullivan et al., 2017). As well,
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behavioural and psychological problems including attention deficit hyperactivity and autism
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spectrum disorders (Davis et al., 2018; Määttä et al., 2006) in children, and neuropsychiatric
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symptoms in adults, have been reported in people with DS (Dekker et al., 2018).
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The last few decades have seen a tremendous increase in the life expectancy of patients with DS reaching an average age of 60 years (Bittles and Glasson, 2004; Carfì et al., 2014). This reflects the advancement in the field of medical research and simultaneously poses considerable challenges to
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the healthcare system in terms of catering to the plethora of phenotypic characteristics and other life
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threatening comorbidities that accompany DS in adulthood.
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Intellectual disability invariably associated with DS, still remains a major challenge to manage by families and healthcare professionals involved in the care of people with DS. Every DS individual presents cognitive and learning deficits in a degree ranging from mild to severe. For example, in a DS population, analysis of 53 females (mean age of 35 years) and of 76 males (mean age of 29 years) resulted in intellectual disability scores of 19% mild, 30% moderate 33% severe and 18% profound, with a sex difference being females with better cognitive abilities and speech production 7
compared with males (Määttä et al., 2006). Of note, enriched environment and specific educational methods were shown to improve cognitive development and intellectual disability scores and biological response as suggested by results obtained in behavioural studies in both mouse models of DS, and DS children (Engevik et al., 2016; Martínez-Cué et al., 2005). However, adults with DS have a high risk for progressive cognitive decline and loss of acquired abilities (see the review
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(Krinsky-McHale and Silverman, 2013).
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Many theories have been proposed to explain DS-related abnormalities in the central nervous system (CNS), including the gene dosage effect, the amplified developmental instability, and the critical region hypotheses (Krinsky-McHale and Silverman, 2013). However, the case of
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monozygotic twins with trisomy of Hsa21 but with discordant phenotypes (Grynberg et al., 2007),
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and the case of subjects with DS phenotype but carrying a partial 21 trisomy of a very restricted
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region coding for not already known genes (34 kb on distal 21q22) (Pelleri et al., 2016), have
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highlighted the likely involvement of other mechanisms to explain the wide phenotypic variation
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occurring in subjects with DS. For instance, epigenetic histone modification and DNA methylation, as well as microRNA regulation of gene expression have also been proposed to play a causal role in the aetiology of DS (Mentis, 2016). Transcriptome maps of human endothelial progenitor cells with
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Hsa21 trisomy obtained by massive–scale RNA-sequencing analysis have revealed up or down-
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regulation of transcripts outside the Hsa21 (Costa et al., 2011). More recently, a meta-analysis, comparing transcript expression levels and profiles of several human tissues and cells with trisomy
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21 with their corresponding diploid, has confirmed the gene dosage hypothesis with 3:2 DS/normal ratio for Hsa21 genes, and listed genes mapped on other chromosomes differentially expressed (Pelleri et al., 2018). Mitochondrial dysfunction due to impairment of key regulatory processes (see the review Valenti et al., 2018), leading to a lower ATP production and deficits in total brain energy, as well as overproduction of reactive oxygen species (ROS) (Valenti et al., 2017, 2016, 2011, 2010), are also 8
believed to be involved in the pathogenesis of DS and in DS-related cognitive impairment. Free radical species, produced by dysfunctional mitochondria, can induce a progressive accumulation of oxidative damage in mitochondrial DNA, and endogenous defence mechanisms against oxidative stress are known to be impaired in DS (Druzhyna et al., 1998). This can in turn lead to early cellular aging and neurodegeneration. It is well established, that the efficiency of mitochondrial
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bioenergetics and dynamics is fundamental for the neurobiological mechanisms underlying intellectual development (for refs see (Khacho and Slack, 2018; Valenti et al., 2014). Aberrant
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mitochondrial energy metabolism and oxidative stress could result in the increased susceptibility of individuals with DS to a large spectrum of diseases such as AD, cardiomyopathy and autism spectrum disorders (Helguera et al., 2013).
Coskun et al. (2017) tested the hypothesis that
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peripheral cells from elderly subjects with DS show dementia-specific and disease-specific
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metabolic features. Using lymphoblastic-cell-lines derived from individuals with DS and DS-with-
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dementia, the study showed that DS cells exhibited a slower growth rate under minimum feeding
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and reduced expression of the autophagy marker LC3-II. Taken together, these findings underscore
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the close relationship between metabolic dysfunction and impaired autophagy in DS (Coskun et al., 2017).
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Several mouse models have been generated in order to study genotype/phenotype correlations in DS and in particular, neurobiological alterations in DS brain (see Table 1). Ts65Dn was the first viable
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trisomy model (Reeves et al., 1995) and was widely used as a DS animal model given that it recapitulates the main phenotypic feature of DS ((Reeves et al., 1995). This model possesses a
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major portion of mouse chromosome 16 (MMU16) carrying some of Hsa21 orthologues at its distal end translocated to the centromeric region of mouse chromosome 17 (MMU17). However, it should be mentioned that Ts65Dn, as well as other mouse models, is not trisomic for all Hsa21 orthologues, and is also trisomic for a number of non-Hsa21 orthologues. Therefore, the use of transgenic and trans-chromosomic mice as models to study DS are vigorously debated. Therefore, 9
other model systems, such as stem cell models have also been proposed to study alterations in neuronal development that occur in DS. For example, induced pluripotent stem cells (iPSCs), obtained from skin or blood cells can be genetically "reprogrammed" to assume a stem cell-like state via specific differentiation protocols, to first generate neural progenitor cells (NPCs), and then human neurons in vitro (Scudellari, 2016). These cells are considered an important tool to
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recapitulate neurodevelopmental stages (Hibaoui et al., 2014) or to reproduce early stages of AD
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type pathology in DS (Dashinimaev et al., 2017).
In this review we report an overview of selected preclinical and clinical studies on both mouse models of DS and humans. A comprehensive search for integrative reviews and original research
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articles published up to December 2018 on relevant aspects of neurobiological alterations and
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therapeutic targets in DS using the PubMed/Medline, ISI and clinicaltrials.gov online databases was
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conducted. The current review begins with a description of critical Hsa21 genes and their targets, as
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well as epigenetic DNA and protein modifications that are likely to be involved in DS phenotype.
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We then discuss how alterations in regulatory signalling and metabolic pathways are critically involved in neurobiological abnormalities associated with DS. Finally, the therapeutic efficacy of selected pharmacological strategies, including naturally occurring phytochemicals to attenuate the
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aberrant metabolic pathways associated with DS are also discussed.
2. Alterations in metabolic and signalling pathways critical for the neuropathology of Down
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syndrome
The neuropathogenesis of DS occurs as a result of a combination of several factors leading to alterations in neuronal es including neurogenesis, neurotransmission and neuroplasticity. Mitochondrial dysfunction, oxidative stress and neuroinflammation, altered glucose metabolism, impairment of homocysteine metabolism, and altered proteostasis and secondary messenger
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signalling pathways (Butterfield and Perluigi, 2018), are indicated as possible contributors in the impairments of both CNS formation and degeneration (Figure 1).
2.1. Impairments in neurogenesis During foetal development, neural stem cells proliferate and differentiate into neurons in a process
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called neurogenesis (Kitamura et al., 2009). Notably, in the hippocampus, neurogenesis occurs postnatally and continues throughout life (called adult neurogenesis) as an adaptive response to
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regulate brain plasticity and memory (Spalding et al., 2013). Reduced neurogenesis is considered among the major neurodevelopmental defects leading to cognitive disability in DS. Results obtained using brains of individuals with DS, DS-derived iPSCs, and NPCs from the hippocampus of DS
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mouse models as experimental systems, showed a decline in proliferation potency, impaired
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neuronal maturation, and neural cell death, which occurred concurrently with alterations to
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neurogenesis in DS (Gimeno et al., 2014; Hibaoui et al., 2014). Data obtained from immunostaining
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experiments using cell proliferation protein markers have shown a reduction in proliferation
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potency in the hippocampal dentate gyrus and neocortical germinal matrix in brains of foetuses with DS starting in the early gestational age (17-23 weeks) (Contestabile et al., 2007; Guidi et al., 2008). The dentate gyrus has a key role in cognition and memory acting as a pre-processor of incoming
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information, which is subsequently processed in the granule cells and pyramidal neurons of the
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hippocampal CA3 (Miyata et al., 2017). A reduction in cell proliferation was also shown in vitro both in neurospheres obtained from the frontal cortex of DS foetuses (Lu et al., 2012) and in NPCs
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obtained from the dentate gyrus of the hippocampus of Ts65Dn mouse model (Valenti et al., 2016). The reduced proliferation potency of neural precursor cells in the DS brain is accompanied by impairments in neuro-differentiation. Immunohistochemical quantification of the number of mature neurons (NeuN-positive cells) and astrocytes (GFAP-positive cells) in both the DG of hippocampus of Ts65Dn mice and hippocampal and para-hippocampal regions of foetuses with Hsa21 trisomy, showed a reduction in the number of neurons and an increase in the number of astrocytes with 11
respect to diploidy (Guidi et al., 2008). Consistently, analysis of iPSCs derived from monozygotic twins discordant for trisomy 21 showed that DS iPSCs exhibit a reduced number of neurons and a shift from neuronal to astroglial and oligodendroglial differentiation. Additionally, neurons also displayed reduced length of neurites (Hibaoui et al., 2014). The reduction in both neural proliferation and differentiation in several brain regions indicates that the impairment in
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neurogenesis is an early event in DS.
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Several mechanisms involved in defective neuronal proliferation and differentiation in DS have been evaluated using mouse and cellular models of DS (Stagni et al., 2018). These include overexpression of some Hsa21 gene products, as well as epigenetic alterations. Herein, we report
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evidence supporting also the crucial role played by mitochondrial dysfunction in the deregulation of
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2.1.1. Genetic deregulation
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neurogenesis in DS.
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The ‘gene-dosage effect’ hypothesis i.e. the 1.5-fold increase of Hsa21 genes, due to an extra copy of Hsa21, has been first suggested to be responsible for the metabolic alterations leading neurological and cognitive impairments in people with DS (Delabar et al., 1993). Importantly,
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genes on Hsa21 encode many transcription factors or regulatory proteins that induce a secondary
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genome-wide transcriptional deregulation, resulting in down-or up-regulation of crucial genes on both Hsa21 and other chromosomes involved in impaired neurogenesis in DS (Rachidi and Lopes,
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2011).
The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) is thought to be a crucial Hsa21 gene strongly implicated in various DS phenotypes as demonstrated in TgDYRK1A transgenic mice over-expressing DYRK1A (Altafaj et al., 2001). Indeed, hyperactivity of DYRK1A protein is known to be involved in the derangement of excitatory-inhibitory balance, generation of 12
neurodevelopmental abnormalities and other behavioural phenotypes of DS associated with cognitive deficits (Ruiz-Mejias et al., 2016). DYRK1A is also associated with regulation of synaptic plasticity and memory consolidation. Amplified gene dosage resulted in defects of brain morphogenesis, low levels of BDNF and mnemonic deficits in DS mice (Guedj et al., 2009). Overexpression of DYRK1A has also been found in the brain of foetuses and adults with DS
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(Lockstone et al., 2007) and in DS iPSCs-derived NPCs (Hibaoui et al., 2014). DYRK1A is present in both the nucleus and cytoplasm of mammalian cells (Figure 2), and appears to have a crucial role
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during neurogenesis and CNS development. Genome-wide analysis of DYRK1A-associated loci reveals that in the nucleus this kinase is recruited to proximal promoters of growth-related genes, actively transcribed by RNA polymerase II, involved in different cellular processes such as
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translation, RNA processing and cell cycle (Di Vona et al., 2015). In addition, DYRK1A
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phosphorylates multiple targets in both the nucleus and the cytoplasm, including among others
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cyclin L2 and cycline D1 (both are involved in cell cycle regulation and neurogenesis), α-synuclein
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(presynaptic regulation), dynamin 1 (which regulates the endocytosis and apoptotic signalling),
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APP, Tau (both involved in AD), synaptojanin 1 (for synaptic transmission), and the cAMP response element binding (CREB), (which regulates diverse cellular responses), as extensively reviewed in (Becker et al., 2014; Duchon and Herault, 2016; Stagni et al., 2018). In particular, it has
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been reported that DYRK1A phosphorylates cyclin D1 at Thr286 inducing its degradation, which in
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turn determines alterations in cell cycle and negative regulation of neural progenitor cell proliferation (Nakano-Kobayashi et al., 2017). An increase in the DYRK1A gene dosage also
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induces elongation of both G1 and S phases. This correlated with a transient increase in the population of intermediate progenitor neurons and overall reduction in the total neuronal output of the postnatal brain (Smith and Calegari, 2015). It is well established that DYRK1A also phosphorylates p53, which leads to induction of p53 target genes and impaired G1/G0-S phase transition, resulting in a reduced proliferation (Park et al., 2010).
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Inhibition of DYRK1A activity by the naturally occurring polyphenol, epigallocatechin-3-gallate (EGCG) ameliorated cognitive behavioural phenotypes and excitatory-inhibitory equilibrium in a DS mouse model (de la Torre and Dierssen, 2012; Guedj et al., 2009; Souchet et al., 2015), highlighting the involvement of DYRK1A gene over-dosage in the regulation of neurogenesis and cognitive impairment in DS (Stagni et al., 2015). A synthetic compound 3-(4-fluorophenyl)-5-(3,4which
is
a
fluoric
derivative
of
3,5-
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dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine,
di(polyhydroxyaryl)-7-azaindole named F-DANDY, has been reported to selectively inhibit
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DYRK1A both in vitro and in vivo (in Ts65Dn mice), improving learning and memory in Ts65Dn mice (Neumann et al., 2018). Leucettine 41, a synthetic congener of Leucettamine B alkaloid derivative, has also been shown to normalize overexpressed DYRK1A in Ts65Dn, Tg(Dyrk1a) and
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Dp1Yey mouse models of DS, by selectively inhibiting DYRK1A, thus improving cognitive
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function (Nguyen et al., 2018). As well, a synthetic compound named ALGERNON (altered
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generation of neurons) was found to inhibit DYRK1A in cultured neural stem cells from Ts65Dn
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mice as well as in vivo in Ts65Dn mice, thereby enhancing proliferation in neural stem cells and
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restoring cognitive function in Ts65Dn mice (Nakano-Kobayashi et al., 2017).
The regulator of calcineurin 1 (RCAN1), also known as DS critical region 1 protein (DSCR1), is an
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endogenous inhibitor of the calcineurin phosphatase and is overexpressed in DS (Fuentes et al.,
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2000). It has been reported to play an important role in DS neurodevelopmental deficits impairing neurotrophin trafficking and inducing alterations in the development of the sympathetic nervous
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system (Patel et al., 2015), in Dp(16)1Yey/+ mice, a mouse model of DS trisomic solely for the human 21q11-q22.3 synthetic region (Table 1) (T. Yu et al., 2010). In TgRCAN1 mice overexpressing the sole RCAN1 gene, the density of dendritic spines on hippocampal pyramidal neurons was reduced and accompanied by a failure to maintain long-term potentiation, strongly suggesting that RCAN1 plays an important role in brain development and its up-regulation likely contributes to the neural deficits associated with DS (Martin et al., 2012). Studies in RCAN1- and 14
DYRK1A–overexpressing mice have shown that DYRK1A, which phosphorylates RCAN1 at Ser112 and Thr192 residues, acts synergistically with RCAN1 to regulate the phosphorylation levels of the Nuclear factor of activated T-cells (NFAT). This transcription factor, after translocation into the nucleus, up-regulates the expression of interleukin 2, with a consequent stimulation of growth and differentiation of T cell response (Arron et al., 2006; Jung et al., 2011).
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NFAT also regulates proliferation and differentiation of neural precursor cells; it has been reported that NFAT activation reduces the percentage of cells in G0/1 phase of the cell cycle and causes cell
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cycle elongation (Serrano-Pérez et al., 2015). Altogether these studies have suggested an important role of DYRK1A/RCAN1/NFAT signalling pathways in the regulation of NPC proliferation (Stagni
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et al., 2018).
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Less studied regarding deficit of neurogenesis in DS is the Hsa21-encoded receptor-interacting
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protein 140 (RIP140), whose murine orthologous protein is named nuclear receptor interacting
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protein 1 (NRIP1). NRIP1, through the interaction of nuclear receptor factors, regulates gene
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expression and controls several metabolic processes in mouse (Fritah et al., 2010). Increased expression of the RIP140 protein has been demonstrated in human hippocampus of people with DS exhibiting strong cognitive disabilities (Gardiner, 2006). Knock-out of NRIP1 in mice results in
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learning and memory deficits, as well as an increased stress response, suggesting an involvement of
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this Hsa21 gene in cognitive function (Duclot et al., 2012). Recently Zhao and co-workers have reported that RIP140 participates in the differentiation of stem cells into neuronal progenitor cells
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through a mechanism mediated by the ERK1/2 pathway (Zhao et al., 2017). Thus, ERK1/2 signalling may provide the molecular basis by which RIP140 participates in neural differentiation.
Cystathionine beta synthase (CBS) is another Hsa21-encoded crucial enzyme that might be involved in altered neurogenesis in DS. It is involved in homocysteine metabolism (Chen et al., 2010). Homocysteine is a mediator of two crucial biochemical processes; activated methyl cycle, 15
and trans-sulfuration pathway (Medina et al., 2001). Its significance can be deduced from the fact that alterations in homocysteine levels is implicated in various diseases including neurological disorders (Blom and Smulders, 2011; Miller, 2003; Schalinske and Smazal, 2012), AD (Chen et al., 2010), and congenital abnormalities, such as neural tube defects, cleft palate and congenital heart
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disease (Blom and Smulders, 2011; Škovierová et al., 2016).
Numerous studies have reported significantly diminished plasma homocysteine levels in individuals
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with DS due to excessive CBS-mediated hyperactivity of homocysteine trans-sulfuration pathway (Gane, B and Bhat, V, 2014; Obeid et al., 2012; Pogribna et al., 2001). The hyperactive transsulfuration pathway also accounts for a decline in tetrahydrofolate generation from 5-
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methyltetrahydrofolate resulting in a deficit of functional folate, which is indispensable for de novo
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synthesis of RNA and DNA (Gane, B and Bhat, V, 2014; Pogribna et al., 2001; Song et al., 2015).
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Interestingly, another study showed how CBS impairment plays a crucial role in both
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neurodevelopmental abnormalities and early neurodegeneration in DS. In that study, analysis of
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CBS-positive neurons and astrocytes in cerebelli from foetuses and adults with DS showed a high level of CBS in granular cell layers during foetal development which correlated to an abnormal number of inhibitory neurons; increased CBS in the adult DS brain have been related to AD-like
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dementia (Kanaumi et al., 2006). A study carried out on Ts1Yah mouse model to evaluate the effect
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on DS etiology of the trisomy of genes located in a subtelomeric portion of Hsa21 (namely Abcg1– U2af1), containing CBS, reported that overexpression of the hippocampal CBS gene was associated
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with improved spatial memory and enhanced long term potentiation (Pereira et al., 2009). Another study, carried out on Ms2Yah mouse model to determine the effect of the monosomy of the genes in the same Abcg1-U2af1 region, reported more improved effects on long-term potentiation and memory (Sahun et al., 2014).
16
As well, several microRNA (miRNA) are also overexpressed in some brain regions in people with DS and are proposed to contribute to neurodevelopmental deficits. It is well established that miRNAs are 18-24 nucleotide long non-coding RNAs and post-transcriptional regulators of gene expression acting by either destabilizing mRNAs or by repressing translation, thus regulating various physiological processes, such as development, proliferation, differentiation and apoptosis
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(Cannell et al., 2008; Catalanotto et al., 2016; Kamhieh-Milz et al., 2014). Hsa21 harbours at least 29 miRNAs, but only five, namely miR-99a, let-7c, miR-125b-2, miR-155, and miR-802 have been
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thoroughly studied and found implicated in DS pathogenesis, as reviewed in (Brás et al., 2018; Mentis, 2016; Sanchez-Mut et al., 2016). Interestingly, miR-155 and miR-802 directly downregulate the epigenetic modulator methyl-CpG binding protein 2 (Mecp2) (Bofill-De Ros et al.,
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2015), and are implicated in another neurodevelopmental disorder, known as Rett syndrome (De
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Filippis et al., 2015; Liyanage and Rastegar, 2014). Overexpression of miR-155 in the brain of
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people with DS also results in the down-regulation of SNX27, a key regulatory protein assuring the
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glutamate receptor recycling whose loss contributes to synaptic dysfunction in DS (Wang et al.,
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2013). Similarly, differentially expressed miRNAs, specifically miR-138 along with its target zeste homolog 2 (EZH2), were also reported in DS foetal hippocampus, indicating their role in
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neurological manifestations of DS (Shi et al., 2016).
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2.1.2 Epigenetic deregulation Over-expression of many Hsa21 genes causes dysregulation of some epigenetic mechanisms in DS
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including DNA methylation, histone modification and chromatin remodelling, and are reported to play a crucial role in learning and memory defects in DS (for a comprehensive review see (Dekker et al., 2014). DNA methylation serves as a major epigenetic modulator of gene expression (Crider et al., 2012; Moore et al., 2013). Incongruity in DNA methylation is an important causal factor in the development of neural tube defects (Blom and Smulders, 2011; Škovierová et al., 2016), and neurological (Moore et al., 2013) disorders. DNA methylation influences multiple aspects of 17
neurogenesis from stem cell maintenance and proliferation, followed by neuronal differentiation and maturation, and synaptogenesis; mutations in proteins involved in the establishment, maintenance and removal of DNA methylation impact brain development and functions (Jobe and Zhao, 2017).
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Anomalous DNA methylation is a common occurrence in trisomy 21. Hyper-methylation of DNA is association with upregulation of DNA methyltransferase (DNMT) genes DNMT3B and DNMT3L
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and downregulation of TET2 and TET3 demethylation genes have also been reported from a study using skin fibroblasts isolated from DS monozygotic twins (Sailani et al., 2015). Several other genes such as TCF7, SH3BP2, CD3Z, NOD2 TMEM131, EIF4E, SUMO3, CPT1B, NPDC1 and
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PLD6 from blood-derived leukocytes and T-lymphocytes of DS individuals exhibited differential
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methylation (Kerkel et al., 2010). Jin and co-workers proposed a role of epigenetic mechanisms in
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the plethora of phenotypic outcomes of trisomy 21. They also showed the presence of global DNA
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hyper-methylation in placental villi cells of DS foetuses and leukocytes from DS adults (Jin et al.,
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2013). Hyper-methylated lymphocytic DNA has also been reported in children with DS (Pogribna et al., 2001). As previously discussed, it should be highlighted that repression of the demethylase Mecp2, secondary to trisomic overexpression of Hsa21-derived miRNAs miR-155 and miR802
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(Bofill-De Ros et al., 2015), may partly contribute to the hyper-methylation and neurochemical
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alterations observed in the brains of DS individuals. hypo-methylation of mitochondrial DNA has also been reported in DS due to a mitochondrial methyl imbalance linked to a reduction in S-
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adenosyl-methionine synthesis (Infantino et al., 2011).
Histone deacetylation and acetylation are other epigenetic mechanisms influenced by some Hsa21 genes. DYRK1A, for example, activates SIRT1 phosphorylation and promotes histone deacetylation (Guo et al., 2010); on the other hand, DYRK1A interacts with NRSF/REST affecting chromatin re-
18
modeling and deregulates the levels of gene clusters essential for neural differentiation leading to neuronal alterations in DS (Lepagnol-Bestel et al., 2009).
2.1.3. Mitochondrial dysfunction Mitochondrial metabolism strongly influences the distinct developmental steps of adult
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neurogenesis (Beckervordersandforth, 2017). Several recent studies reported that activation of mitochondrial biogenesis and function induces a metabolic shift from glycolysis to oxidative
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phosphorylation, which mediates the cell fate decision to start the neurogenesis process inducing neural stem cells to generate actively proliferating intermediate progenitor cells which differentiate into mature neurons. Disturbances in mitochondrial function and signalling lead to changes in the
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cell fate and negatively affect the neurogenesis and neuroplasticity processes (for refs see the
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reviews Arrázola et al., 2018; Beckervordersandforth, 2017; Khacho et al., 2019).
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In this light, we have already reviewed and discussed how deficits in neural energy due to
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mitochondrial dysfunction is critical for the aetiology of DS (Valenti et al., 2018, 2014). Mitochondrial dysfunction is an early event in DS and is even considered to be responsible for nondisjunctional disabilities of chromosomes during meiosis in embryos that results in aneuploidies
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like DS (Coskun and Busciglio, 2012; Eichenlaub-Ritter et al., 2011; Schon et al., 2000). The
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presence of significantly high ROS and disrupted mitochondrial network has been reported in DS human fibroblasts as well as mouse embryonic fibroblasts (Zamponi et al., 2018).
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Oligonucleotide microarray analysis profiling of the transcriptome of Hsa21 genes of DS foetal hearts showed downregulation of mitochondrial genes specifically those encoding for mitochondrial enzymes (Conti et al., 2007). Similar downregulation of mitochondrial genes along with mitochondrial morphological alterations and respiratory activity aberrations were also observed in DS foetal fibroblasts and neural progenitor cells (Izzo et al., 2017b; Piccoli et al., 2013; Valenti et al., 2017). Accordingly, a recent systematic proteome and proteostasis profiling study in human DS 19
fibroblasts revealed significant downregulation of the mitochondrial proteome, which strongly concurs to the DS phenotype (Liu et al., 2017). However, one study proposed that downregulation of mitochondrial function could be an adaptive mechanism to prevent ROS generation and subsequent cellular damage (Helguera et al., 2013).
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Mitochondrial phenotype in DS is characterized by reduced efficiency to produce ATP through oxidative phosphorylation, decreased respiratory capacity, impaired ability to generate
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mitochondrial membrane potential, as well as alterations in mitochondrial structure and dynamics (see the review (Valenti et al., 2018). The molecular bases for mitochondrial dysfunction and cell energy deficiency in DS have been well studied. An overview of the Hsa21 genes and key
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regulatory signalling pathways involved in mitochondrial dysfunctions in DS have been recently
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reviewed (Izzo et al., 2018; Valenti et al., 2018). In particular, down-regulation of PGC-
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1α/Sirt1/AMPK axis is involved in the impairment of mitochondrial biogenesis (Piccoli et al., 2013;
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Valenti et al., 2016). Alterations to the expression of dynamin-1-like protein (Drp1), mitofusin 2
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(Mnf2) and optic atrophy 1 (Opa1) has been associated with alterations in mitochondrial structure and network (Izzo et al., 2017b; Valenti et al., 2017). In addition, a decrease in cAMP levels and protein kinase A (PKA)-mediated phosphorylation of the mitochondrial respiratory chain (MRC) in
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DS lead to a reduced catalytic efficiency of MRC complex I and ATP synthase with a consequent
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decline in ATP production, reduced cellular energy, an increase in ROS produced by the mitochondria and oxidative stress (Valenti et al., 2011, 2010). Overexpression of RCAN1 in TG
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mice has been shown to promote mitochondrial dysfunction (Wong et al., 2015) and causes DS-like immune dysfunction as shown by Martin and co-workers (Martin et al., 2013). In addition, the miRNAs let-7c and miR-155, have been reported to target genes involved in the regulation of mitochondrial function (Izzo et al., 2017a). Finally, overexpression of the Hsa21-encoded Ets-2 induces translocation of cytochrome c by mitochondria and induction of mitochondrial death pathway leading to degeneration of DS cortical neurons (Helguera, 2005). 20
Repair mechanisms against oxidative stress mediated damage to mitochondrial DNA are also known to be compromised in DS (Druzhyna et al., 1998). Recently, alteration in mitochondrial dynamics and bioenergetics due to deregulation of Drp1 expression and activity has also been shown to impair hippocampal neurogenesis in Ts65Dn mice (Valenti et al., 2017) and the rescue of
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mitochondrial functions restores normal proliferation of NPCs from the hippocampus of Ts65Dn mice (Valenti et al., 2016). This data confirms the hypothesis of Beckervordersandforth that
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mitochondrial metabolism strongly regulates adult neurogenesis (Beckervordersandforth, 2017).
2.2. Impairments in neurotransmission
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The interplay of both inhibitory and excitatory neurotransmitters plays a major role in cognition and
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neurodevelopmental processes (Cohen Kadosh et al., 2015). Derangement in this excitatory-
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inhibitory equilibrium has long been implicated in DS-associated neuronal impairments (Créau,
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2012). Herein we review and discuss the molecular mechanisms of the changes in the main
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neurotransmission processes in DS (see Figure 2).
2.2.1. GABAergic transmission
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The main inhibitory neurotransmitter in humans, γ-aminobutyric acid (GABA), acts by two
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receptors families, GABAARs and GABABRs. GABAARs are ligand-gated chloride channels composed of a combination of several subunit subtypes (Olsen and Sieghart, 2009). GABABR is a
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class of G-protein coupled receptor (GPCR) that associates with a subset of G-proteins controlling specific ion channels (Padgett and Slesinger, 2010) GABABR is composed by three different subunits reported to modulate both synaptic transmission and postsynaptic responses by a direct interaction of Ca2+ and K+ channels, respectively (Pinard et al., 2010).
21
In postnatal development or in axonal compartments, GABAAR activation induces membrane depolarization due to a higher intracellular Cl- concentration (Zorrilla de San Martin et al., 2018). In adult neurons, GABAAR becomes hyperpolarized due to a change in the Cl- balance to lower intracellular Cl- concentration and exerts an inhibitory function (see the review (Herbison and Moenter, 2011). Interestingly, recent studies have shown a reversal of function of GABA AR
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signalling in the hippocampus of Ts65Dn mice which was found to be excitatory rather than inhibitory, generated by an inversion in the direction of Cl- currents due to an increase in the
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expression and activity of the Cl- cotransporter NKCC1 (Contestabile et al., 2017; Deidda et al., 2015).
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Numerous studies on GABAergic transmission in DS have been performed in mouse models and in
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Ts65Dn mice where GABA transmission in neurons was found to be increased. Alterations in the
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KCNJ6 gene, which encodes the subunit 2 of the GIRK channel (GIRK2/Kir3.2), and maps to
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Hsa21, provided the first direct association between DS and GABAergic transmission (Hattori et
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al., 2000; Ohira et al., 1997). An extra KCNJ6 copy led to increased mRNA and protein expression of GIRK2 in the hippocampus, cortex and midbrain of Ts65Dn mice (Harashima et al., 2006). Subsequently, GABAB/GIRK currents were shown to increase in cultured primary hippocampal
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neurons (Best et al., 2007), CA1 pyramidal neurons and dentate gyrus granule cells from acute
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slices of the Ts65Dn hippocampus (Best et al., 2012; Kleschevnikov et al., 2012). This increase in neuronal GABAB/GIRK signalling in Ts65Dn mice is likely to enhance GIRK-mediated shunting
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inhibition, and reduces excitatory PSPs, and alter neuronal passive properties which is likely to affect neuronal excitability and plasticity (Koyrakh, 2005; Lüscher et al., 1997).
Similarly, genetic restoration of GIRK2 to disomy in Ts65Dn mice attenuated elevations in GABAB-triggered currents in CA1 pyramidal neurons (Joshi et al., 2016) and dentate gyrus granule cells (Best et al., 2012; Kleschevnikov et al., 2012). 22
Association of GABAergic over-inhibition and cognitive and learning deficits in DS was also demonstrated in a study carried out by Fernandez et al., 2007. The study showed improvement in cognition and long term potentiation (LTP) of Ts65Dn mice on chronic treatment with the GABAA antagonists Picrotoxin (4 weeks) and Pentylenetetrazole (1 year), respectively) (Fernandez et al., 2007). Similar improvements in learning and memory of Ts65Dn mice was also reported following
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administration of selective inverse agonists for α5- GABAA receptor subtype (Braudeau et al., 2011).
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Of note, a discrepancy between the increase in GABA transmission in mouse models and a reduction in GABA concentrations in human foetal brains with DS (Whittle et al., 2007) and in brains of children with DS as measured by magnetic resonance imaging (Śmigielska-Kuzia et al.,
N
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2010) has been previously reported .
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GABAergic dysfunction disrupts the optimal excitatory/inhibitory synaptic balance in DS
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depolarizing GABA transmission and leading to impairments in synaptic plasticity and learning and
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memory deficits in DS (Deidda et al., 2014; Fernandez et al., 2007; Souchet et al., 2015; Zorrilla de San Martin et al., 2018). In line with these findings, enhanced excitability and reduced GABA inhibition has also been reported in cerebellar granule cells from Ts65Dn mice (Das et al., 2013;
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Szemes et al., 2013; Usowicz and Garden, 2012). Treatment with the α5-containing GABAAR
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negative modulator RO4938581, but not bumetanide, ameliorated hyperactivity in Ts65Dn mice (Deidda et al., 2015; Martinez-Cue et al., 2013). This suggests that additional mechanisms apart
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from altered GABA signalling may be associated with the hyperactive phenotypes in Ts65Dn mice. For example, treatment with the GluN2B-selective antagonist Ro25–6981 (Hanson et al., 2013) or EGCG, an inhibitor of the DS triplicated kinase DYRK1A (Xie et al., 2008), the monoacylglycerol lipase inhibitor JZL184 (Lysenko et al., 2014), the neuro-hormone Melatonin (Corrales et al., 2013), the Sonic Hedgehog agonist SAG1.1 (Das et al., 2013), and the selective serotonin reuptake inhibitor fluoxetine (Begenisic et al., 2014; Bianchi et al., 2010; Guidi et al., 2014), have each been 23
shown to restore CA3-CA1 LTP and/or behavioural performances in vulnerable Ts65Dn mice. GABAergic synaptic transmission has also been shown to be modulated by the Akt-mTOR pathway, which has been reported to be hyper-activated in the hippocampus of Ts1Cje mice, a murine model of DS, leading to an increase in local dendritic translation and synaptic plasticity
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impairment (Troca-Marín et al., 2014).
2.2.2. Glutamatergic transmission
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Apart from alterations in GABAergic signalling, anomalous glutamatergic transmission and Nmethyl-D- aspartate receptor (NMDAR) signalling have been reported in the pathobiology of DS. For example, studies have reported delayed development and reduced production of excitatory
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glutamatergic neurons in the cortex of Ts65Dn mice (Chakrabarti et al., 2010, 2007; Guidi et al.,
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2014; Tyler and Haydar, 2013). As well, a lower density of glutamatergic synapses was observed
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using electron microscopy in the cortex and hippocampus of Ts65Dn mice (Ayberk Kurt et al.,
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2004; Chakrabarti et al., 2007; García-Cerro et al., 2014; Guidi et al., 2013; Kurt et al., 2000; Rueda
Weick et al., 2013).
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et al., 2010; Stagni et al., 2013), and in human DS iPSCs-derived neurons (Hibaoui et al., 2014; Despite these findings, electrophysiological studies that investigate the
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involvement of glutamatergic signalling in trisomic mice are nascent in the current literature.
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Impaired glutamatergic transmission has been proposed to account for behavioural disability and learning and memory deficits in both individuals with DS and animal models (Boada et al., 2012;
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Kaur et al., 2014). This has been shown in the Ts2 mouse model for DS, having in triplicate a short Hsa21 region containing APP (Brault et al., 2015), which exhibited a shortage in the levels of glutamate in the hippocampus (Kaur et al., 2014). The reduced glutamate levels resulted in decreased efficiency in nest building, object finding and entering alternate arms of a Y-maze (Kaur et al., 2014). A failure in systemic glutamate uptake, which has been reported to be independent of age has been demonstrated in platelets and fibroblasts from DS individuals (Begni et al., 2003). 24
Deficits in glutamate levels in the hippocampal region (Reynolds and Warner, 1988) and reduction of glutamate, norepinephrine and serotonin levels have also been demonstrated in para-hippocampal gyrus of post-mortem tissue samples from the human DS brain (Risser et al., 1997). This disparity in inherent glutamate uptake in DS is attributed to oxidative stress, as a result of mitochondrial dysfunction, and has also been correlated to Hsa21 gene products and overexpression of the Hsa21-
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encoded proteins APP and superoxide dismutase 1 (SOD1), which are known to further exacerbate
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neurodegeneration and intellectual disability in people with DS (Begni et al., 2003).
2.2.3. Other synaptic transmissions
DS is also associated with progressive noradrenergic neuronal loss in locus coeruleus. Locus
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coeruleus is built by noradrenergic neurons located in the brainstem, in close proximity to the fourth
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ventricle (Aston-Jones et al., 1994). It directs noradrenergic transmission to the majority of brain
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regions involved in cognitive function (Phillips et al., 2016). Noradrenergic loss has been shown to
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propagate cholinergic degeneration, neuroinflammation and memory loss in Ts65Dn mice
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(Lockrow et al., 2011). Restoration of noradrenergic neurotransmission using a prodrug for norepinephrine or a β-adrenergic receptor agonist, reversed cognitive dysfunction in Ts65Dn mouse model of DS (Salehi et al., 2009). Phillips and colleague demonstrated that low levels of
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noradrenaline and impairment of noradrenergic transmission correlated with the occurrence of
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neurodegeneration and dementia in adults with DS. Indeed, detection of low levels of noradrenaline has been found in the cortical and subcortical regions of the postmortem brain of DS people with
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dementia, and in particular, the occurrence of low serum levels of the noradrenaline metabolite 3methoxy-4-hydroxy phenylglycol (MHPG), increased the risk of developing dementia in DS adults by ten-fold (Phillips et al., 2016).
A number of studies have demonstrated disturbances in the cholinergic system in DS, and this may be likely due to alteration in acetylcholine metabolism with possibly significant relationships to 25
AD-like symptoms in DS adult, since impaired acetylcholine metabolism has been reported in the AD brain (Carvajal and Inestrosa, 2011). Reduction in the cholinergic neurotransmitters choline acetyltransferase has also been reported in cortical and sub-cortical regions of DS adult brain tissues when evaluated in frozen post mortem brain tissues of people with DS (Godridge et al., 1987). In Ts65Dn mice, basal forebrain cholinergic neurons degenerate with age and may contribute to
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memory impairments (Chang and Gold, 2008; Granholm et al., 2000). Additionally, choline acetyltransferase activity was increased in the cortex and hippocampus and may likely compensate
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for the reduction in the number of cholinergic neurons (Contestabile et al., 2006).
It has been well established that the serotonergic system is impaired in DS (Bar-Peled et al., 1991;
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Whittle et al., 2007). The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) is central for
N
regulation of a wide range of physiological processes in the CNS such as neurogenesis, neuronal
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morphology and synaptogenesis (see the review (Daubert and Condron, 2010), and has been
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implicated in the regulation of mood, cognitive processes and mediating the release of hormones
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(Hoyer et al., 1994). Thirteen diverse 5‐HT receptors have been identified, twelve of which belong to the GPCR superfamily (Van Oekelen et al., 2003). In particular, analysis of the serotonin 5HT1A receptor in DS brains showed that its levels increase during early development but decreases
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below normal levels at the birth (Bar-Peled et al., 1991). In addition, reduced serotonin levels are
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present in the para-hippocampal gyrus and frontal cortical pole of adults with DS (Risser et al., 1997). Given that impaired serotonin uptake can lead to a reduction in the number of neurons in the
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adult brain (Whitaker-Azmitia, 2001), Bianchi and co-authors discussed how alterations in the serotonergic systems, occurring during early life in DS, could contribute to impaired neurogenesis in DS brain and how it may be corrected (Bianchi et al., 2010). London and co-authors suggested that DYRK1A overexpression might be associated with the modification of monoamine neurotransmitters including serotonin; indeed, the transgenic mice for the DYRK1A gene 26
(mBacTGDYRK1A) showed a dramatic reduction of the serotonin contents in several brain areas especially in the hypothalamus (London et al., 2018).
Additionally, a histaminergic deficit has been proposed to contribute to cognitive impairment in DS.
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More specifically, a reduction of histamine-releasing factor (HRF) in the brain of people with DS has been correlated to a decrease in histamine levels associated with cognitive decline and AD-like
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dementia in DS (Kim et al., 2001).
2.3. Impairments in neuroplasticity
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Neuroplasticity is an intrinsic adaptive ability of the nervous system in response to the changing
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milieu, continuous neural activity, learning, and experience (Demarin and Morović, 2014). This
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adaptation can range from functional modulations, such as alterations in neurochemical
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transmission, modulation of dendritic functions, long-term potentiation, or structural adaptations (Demarin and Morović, 2014; Ruge et al., 2012) that include processes from synaptogenesis and
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neurogenesis (Demarin and Morović, 2014; Fuchs and Flügge, 2014) to the revival and reformation of the existing synapses and signalling network (Mundkur, 2005). Basically, neuroplasticity
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accounts for learning and memory, capability of the nervous system and is also responsible for regaining lost abilities of the damaged neuronal system through structural and functional
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rehabilitation (Kleim and Jones, 2008).
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As has been elaborated in this review, DS is a manifestation of abnormalities in neurotransmission, synaptic and neurogenesis impairments. However, neuroplasticity has been also reported to be aberrant in DS (Cramer and Galdzicki, 2012; Dierssen et al., 2003; García-Vallejo et al., 2018; Gardiner et al., 2010). Impaired neuroplasticity in DS is associated with cognitive deficits, and various structural and functional incongruence (Cramer and Galdzicki, 2012), such as impaired 27
dendritic maturation and reduced dendritic length (Takashima et al., 1994), morphological aberration and deficits in the number of dendritic spines (Marin-Padilla, 1976; Purpura, 1975; Suetsugu and Mehraein, 1980; Weitzdoerfer et al., 2001) and reduced synaptic contacts (Rueda et al., 2012). Therefore, improving neuroplasticity seems to be an additional strategy to correcting cognitive impairments in DS. This is because neuroplasticity can reform as well as replenish
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neuronal structures, thus re-establishing the neuronal communication network (García-Vallejo et al.,
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2018; Kays et al., 2012).
Neuronal and synaptic plasticity are known to be modulated by experience-dependent learning. Therefore, experience-dependent cognitive training could prove to be helpful in ameliorating
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cognitive and intellectual disabilities in DS (Bartesaghi et al., 2015). Cognitive training along with
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EGCG treatment has been shown to improve memory and adaptive behaviour in DS subjects in a
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phase II clinical trial (ClinicalTrials.gov Identifier: NCT01699711) (de la Torre et al., 2016). As
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well, providing more spacious and amiable housing conditions to Ts65Dn mice along with EGCG
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treatment improved cognitive functions via increases in dendritic spine density of cornu ammonis 1, and restoration of the balance of inhibitory and excitatory synaptic markers of the cornu ammonis 1
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and dentate gyrus back to normal ranges (Catuara-Solarz et al., 2016).
DYRK1A gene also plays a pivotal role in modulation of brain plasticity and is known to be
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influenced by environmental stimulation through visual-spatial training (Bartesaghi et al., 2015; Pons-Espinal et al., 2013). A study conducted in the year 2009-2010 showed the efficacy of Wii
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gaming technology (that creates virtual reality) in improving sensorimotor functioning in children with DS. Wii gaming aimed at relaying extensive sensorimotor neuronal activity in DS children through mirror mechanism thus targeting experience dependent modulation of neuroplasticity (Wuang et al., 2011).
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Alterations in plasticity have also been observed in various animal models of DS, such as Ts65Dn and Ts1Cje mouse models. In the Ts1Cje mouse model, the trisomic region of MMU16 is translocated to MMU12 rendering it partially trisomic (Davisson, 2005) (Table 1). Both Ts65Dn and Ts1Cje mouse models exhibit abnormality in structure of pyramidal neurons and dendritic spines, as well as impairment of synaptic plasticity. Ts65Dn mice also display impairment of
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experience-dependent neuroplasticity (Dierssen, 2012). The partially trisomic ts1Rhr mouse model (Gupta et al., 2016), displays structural aberrance in dendritic spines and reduced spine density in
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facial dentate. It also exhibits impairment of synaptic plasticity and long-term potentiation in the hippocampus. This mouse model displays morphological aberrations in dendritic spines as well as impairments in neurogenesis. As well, the Kcnj6 transgenic mouse model exhibits functional
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alterations in excitatory synaptic plasticity and long-term depression (Dierssen, 2012). Another
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transgenic mouse model, the DYRK1A bacterial artificial chromosome transgenic mouse model
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(mBACtgDyrk1a) which overexpresses DYRK1A, exhibits enhancement in spine density in the
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pyramidal neurons of prefrontal cortex (Thomazeau et al., 2014). Bidirectional alteration in
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plasticity with impairment in both NMDAR-mediated LTP and endocannabinoid mediated long term depression (LTD) in the hippocampus is also a prominent feature of mBACtgDyrk1a (Ahn et al., 2006; Thomazeau et al., 2014). It also exhibits increases in expression of proteins associated
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with the inhibitory GABAergic pathway and decreases in the expression of proteins of the
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excitatory glutaminergic pathway (Souchet et al., 2014).
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2.3.1. Astrocyte-mediated synaptic dysfunction
Astrocytes play a critical role in the regulation of synaptic plasticity and memory formation (Adamsky and Goshen, 2018; Chung et al., 2015). DS astrocytes have been recognized to have a direct involvement in the reduced synaptic density and abnormal dendritic spine structure and function (Torres et al., 2018). Indeed, during brain development, astrocytes secrete some factors able to induce the formation of functional synapses between neurons (Clarke and Barres, 2013). 29
The astrocyte-neuron interaction is mediated by direct cell-to-cell connection as well as by a complex group of astrocyte-produced molecules, namely “astrocyte secretome” that dynamically changes according to neuronal activity and astrocyte activation (Clarke and Barres, 2013; Kıray et al., 2016). Both neurons and astrocytes in DS show a marked reduction in the thrombospondin 1 (TSP-1) protein expression, an astrocyte-secreted protein having a powerful effect on the
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modulation of both spine number and morphology when evaluated in post mortem foetal brain cell cultures (Garcia et al., 2010; Torres et al., 2018). Depletion of TSP-1 from normal astrocytes
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induced severe changes in spine morphology, while reinstatement of TSP-1 levels rescued the deficit in astrocyte-mediated spine and synaptic morphology. As well, iPSC-derived astrocytes have been shown to have a negative impact on synaptogenesis in DS, due to hyper-activation of the
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mTOR pathway in neurons, and possibly contributing to DS neuropathogenesis (Araujo et al.,
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2.4. Neurodegeneration
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2017).
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Neurodegeneration and the high risk to develop amyloid neuropathology with AD-like symptoms are part of the neurobiological alterations occurring in individuals with DS in adult age. Several neuroimaging researches have long showed that adult DS persons display typical brain alterations
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occurring in AD (Beacher et al., 2009; Lin et al., 2016; Sabbagh et al., 2015; Teipel and Hampel,
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2006). In a study carried out on both AD and DS subjects with dementia, high similarity was reported in the neuropsychological profiles of the two disease groups (Dick et al., 2016). In a recent
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study, evaluation of brain 3D anatomical images and cognitive status of people with DS with an age of 40 years or older revealed a relationship between cognitive deterioration and severity of specific anatomical changes, such as ‘volume reduction in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus’ (Pujol et al., 2018) which indicate early progression of cognitive impairment toward AD in adults with DS. In the next
30
section, we report data that disclose crucial mechanisms and pathways involved in early neurodegeneration in DS.
2.4.1. Amyloid pathway APP gene product encoded by Hsa21 represents a prominent component of the amyloid cascade
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hypothesis of early manifestation of AD in the DS population. APP gene expression in the DS brain was found to be 1.6 fold higher than in the euploid brain and thought to be responsible of the
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accumulation of the plaques containing fibrillar β-amyloid (Aβ) peptide (Lee et al., 2017; Mao et al., 2003). The neurotoxicity of Aβ has been attributed to microglia activation and increased oxidative stress production (Zana et al., 2007). Alteration of the main pathological hallmarks of AD Aβ-containing
plaques,
and
neurofibrillary
tangles
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(including
(NFT)
containing
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hyperphosphorylated tau protein) are similar in DS and AD (Rafii et al., 2015; Tamaoka, 1998;
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Tapiola et al., 2001). Aβ appears to have a similar pattern in DS and sporadic AD and the C-labeled
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Pittsburgh compound B (PiB), used to image Aβ plaques in the brains, showing early striatal
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binding, which is similar to that observed in familial AD. Similarly, tangles appear to occur early in the hippocampus in DS as well in AD (see the review (Head et al., 2016). Production of ROS and oxidative stress, as well as energy depletion by mitochondrial dysfunction are involved in
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intracellular accumulation of Aβ and the pathogenesis of neurodegeneration in DS (Busciglio et al.,
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2002; Paola et al., 2000). As well, activation of the mTOR signalling pathway linked to tau hyperphosphorylation and Aβ generation have been recently shown to correlate with APP triplication and
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neurodegeneration in DS (Di Domenico et al., 2018). Interestingly, alterations in protein quality control mechanisms, such as ubiquitin-proteasome and autophagy, are believed to induce accumulation of Aβ peptides and hyper-phosphorylated tau proteins in the DS brain, and has been proposed to be directly or indirectly involved in early neurodegeneration in DS (Di Domenico et al., 2013; Granese et al., 2013; Nabavi et al., 2018).
31
2.4.2. Oxidative stress, mitochondrial dysfunction and neural cell death Enhanced production of ROS is an attribute that is evident in DS since the embryonic stage (Busciglio and Yankner, 1995; Perluigi and Butterfield, 2012), resulting in apoptotic neuronal death and intellectual disability (Busciglio and Yankner, 1995). However, there are a number of in vitro and in vivo studies that support a link between the accumulation of oxidative stress and neuronal
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cell death, considering that neurons are particularly vulnerable to damage and neurodegeneration (for refs see (Barone et al., 2017). ROS, which include volatile hydrogen peroxide, superoxide
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anions, and hydroxyl radicals are produced under physiological conditions by aerobic respiration and several catabolic and anabolic processes (Halliwell, 1991). Recently, we discussed how mitochondrial dysfunction, due to Hsa21 gene overexpression-dependent deregulation of signalling
U
pathways controlling mitochondrial functions, is central in the etiological mechanisms leading to
N
oxidative stress, cognitive decline, early aging and AD-like dementia in DS (Valenti et al., 2018).
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Thus, mitochondrial dysfunction is not only involved in neurodevelopmental impairment (as
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discussed in the paragraph 2.2.3) but also in neurodegenerative processes, leading to cognitive
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decline in DS. The mitochondrial respiratory chain and in particular, complexes I and III, are the major source of production of the superoxide anion, generated by electron leakage during electron transport, that is converted into H2O2 and O2 by the mitochondrial-MnSOD (Raha and Robinson,
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2000). Impaired mitochondrial respiratory chain and disruption in oxidative phosphorylation can
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lead to a decrease in mitochondrial ATP production and an increase in ROS (Alfadda and Sallam,
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2012).
We have previously demonstrated that dysfunctional mitochondrial complex I in DS cells overproduces ROS in DS human skin fibroblast cell lines (Valenti et al., 2011). Under physiological conditions, ROS are quickly removed before they can cause cellular dysfunction. However, DS cells are not able to efficiently scavenge ROS overproduction and consequently are more susceptible to oxidative damage. Indeed, the elevated intracellular levels of ROS in DS have long 32
been proposed to occur as a direct consequence of overexpression of the SOD1, which plays a crucial role in the metabolism of superoxide radicals and scavenging of ROS (Créau, 2012), and whose overexpression has been indicated in the formation and accumulation of oxidative stress in DS (Rodríguez-Sureda et al., 2015). Hydrogen peroxide generated as a result of superoxide radical metabolism by SOD is further converted to water by catalase (CAT) and glutathione peroxidase
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(GPX). Therefore, an imbalance in SOD/GPX and CAT ratio exacerbates cytosolic ROS accumulation (de Haan et al., 1995). An imbalance in SOD/GPX ratio has been reported in all DS
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tissues (Barone et al., 2017; de Haan et al., 1995; Perluigi and Butterfield, 2012).
Alterations to iron metabolism for deregulation of redox homeostasis in DS has also been recently
U
proposed (Barone et al., 2017). A redox proteomic analysis of brains of people with DS under the
N
age of 40 compared with age-matched controls, revealed accumulation of protein carbonyls (Di
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Domenico et al., 2013), suggesting that both an increase in oxidative stress and reduced clearance
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of oxidized proteins, possibly due to an impairment in proteostasis network (Aivazidis et al., 2017),
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may contribute to early neurodegeneration in DS.
3. Proposed pharmacological intervention and their targets in Down syndrome
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Various pharmacotherapies have been proposed in DS, mainly for improving cognitive behaviour.
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Many drugs that have shown to be effective in mouse models of DS have prompted clinical trials in young adults or children with Hsa21 trisomy. Some clinical studies have reported significant
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adverse effects that have diminished their translational impact or clinical efficacy (de la Torre and Dierssen, 2012). Herein, we will present and discuss drugs already approved for human use and being tested in clinical trials as promising therapeutic strategies for DS (see Figure 2 and Table 2). Their underlying targets and mechanisms of action in relation to DS and potential pitfalls for their use in human, if any, will also be evaluated.
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3.1. Bumetanide and basmisanil (RG1662) The Na-K-Cl cotransporter 1 (NKCC1) has been reported to be upregulated in the hippocampus of Ts65Dn mouse model of DS and considered to be responsible for aberrant GABA AR signalling, which is found to be excitatory rather than inhibitory (see paragraph 2.1.1). This incongruity in GABAAR signalling is believed to be responsible for the impairment of LTP and LTD. LTP and
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LTD are characterized by the strengthening or weakening (respectively) of synaptic efficiency, following specific stimulation protocols and provides information on learning and memory
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efficiency (Contestabile et al., 2017). Bumetanide, NKCC1 inhibitor, capable of reversing GABAAR signalling, has been shown to be beneficial in improving hippocampal synaptic plasticity and enhancing memory in the Ts65Dn mouse model (Contestabile et al., 2017; Deidda et al., 2015).
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Targeting GABA transmission, and in particular Cl- cotransporters seems to be very effective in
N
improving cognitive deficits in DS. However, the bumetanide effect is not maintained after the
A
treatment is ceased (Deidda et al., 2015), thus presuming a lifelong treatment with this drug.
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Bumetanide is an FDA-approved diuretic drug for the treatment of acute pathologies. A limitation
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for the long-term use of bumetanide to correct cognitive impairment in DS is that chronic consumption of this diuretic could have adverse effects on renal function. RG1662 or Basmisanil is a negative allosteric modulator of α5-GABAAR, developed by Hoffmann-
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La Roche Ltd (RO4938581) (Mohler, 2012; Potier et al., 2014). It was found to be efficacious in
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rescuing cognitive and hippocampal synaptic deficits in the Ts65Dn mouse model (Martinez-Cue et al., 2013). Braudeau and colleagues (2011) reported that α5-selective GABAAR inverse agonists are
A
able to restore cognitive function in a DS mouse model. These results assisted the hypothesis that altering the GABAergic-mediated balance between inhibitory and excitatory neurotransmission can competently alleviate cognitive impairments in DS in preclinical models (Braudeau et al., 2011).
Despite the promising results obtained in pre-clinical trials, the phase II multicentre, double blind clinical trial of RG1662 (a derivative of RO4938581) in DS subjects namely CLEMATIS 34
(ClinicalTrials.gov identifier: NCT02024789) did not obtain any significant outcomes to ameliorate cognitive disabilities in DS population as reported by a La Roche statement (from the web site: https://ds-int.org/node/3547).
3.2. Fluoxetine
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Fluoxetine is a selective serotonin reuptake inhibitor generally used as an antidepressant in adults but has also been reported to modulate the immune system (Di Rosso et al., 2016). It has been
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shown to stimulate survival as well as neurogenesis in the dentate gyrus of the Ts65Dn mouse model (Bianchi et al., 2010) and to restore functional connectivity of the synaptic network of the hippocampus in Ts65Dn mice (Stagni et al., 2013). Fluoxetine successfully produced favourable
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morphological changes in dendritic architecture of the granule cells of Ts65Dn mice during the
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earliest phases of development resulting in proper maturation of granule neurons which is
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considered to be a key factor to rescue neurogenesis and neurodevelopmental defects in DS mouse
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model (Guidi et al., 2013). In the granule and subgranular cell layer of dentate gyrus of Ts65Dn
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mice, fluoxetine treatment promoted proliferation and survival of these hippocampal cells, thus resulting in enhanced neurogenesis (Clark et al., 2006). In addition, prolonged oral treatment with fluoxetine in adult Ts65Dn mice has been shown to regularize GABA release, improving the spatial
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memory skills and recovering hippocampal synaptic plasticity (Begenisic et al., 2014). On a
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positive note, treatment with fluoxetine in the perinatal period resulted in long-term improvements on cognitive impairment and prevented early signs of AD-like pathology in adult Ts65Dn mice
A
(Stagni et al., 2015). Beneficial effect in neuronal precursor proliferation potency and dendritic development were also reported in 2-day-old Ts65Dn mice (Guidi et al., 2014). Fluoxetine has been proposed as a potential prenatal pharmacotherapy able to improve foetal hippocampal neurogenesis and improper brain formation (Kuehn, 2016). However, many adverse effects have been reported following long-term treatment of this drug (Riediger et al., 2017), which could limit the continual use of fluoxetine during infancy and adolescence. 35
3.3. Memantine Memantine is a non-competitive NMDA receptor antagonist proposed to improve glutamatergic transmission to ameliorate memory, behaviour and cognitive impairment (Costa et al., 2008; Rueda et al., 2010). An increase in brain derived neurotrophic factors has also been reported in the
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hippocampus and frontal cortex of Ts65Dn mice following treatment with memantine (Lockrow et al., 2011). A pharmacokinetic study inTs65Dn mice revealed that memantine can transfer to the
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offspring through placenta and maternal milk (Victorino et al., 2017). The memory enhancing effect of memantine is thought to be a consequence of its NMDA receptor antagonism mediated blocking of excessive calcium influx (Lipton, 2004) which is known to mediate disparities in neuronal
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signalling involved in memory and cognition (Parsons et al., 2007). As well, memantine has been
N
shown to alleviate long-term depression in the hippocampus of Ts65Dn mice which has been
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proposed to be another possible mechanism for its memory enhancing effects in DS (Scott-McKean
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and Costa, 2011). Despite the promising outcomes obtained for cognition and memory
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enhancement in DS mouse models, memantine seems to fail to re-capacitate cognition and enhance memory in DS adults. Indeed, after a randomised double-blind placebo-controlled trial with adults (>40 years) with DS, with and without dementia (ISRCTN registry identifier: ISRCTN47562898),
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Hanney and colleagues concluded that there were non-significant differences between treated and
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placebo groups and that memantine, although well-tolerated, is not an effective treatment to correct dementia in DS (Hanney et al., 2012). On the contrary, Boada and colleagues reported beneficial
A
effects of memantine on cognition in a pilot randomized double blinded trial with young adult with DS (between the ages of 18 and 32 year (ClinicalTrials.gov identifier: NCT01112683). Although they found no significant differences between the memantine treated and placebo group in paired learning and pattern recognition memory, which were the two main primary outcomes of the trial, they found a significant improvement in the memantine group in one of subset memory outcomes
36
and only infrequent and mild adverse events (Boada et al., 2012), suggesting the importance to explore other biochemical biomarkers in future clinical studies with this drug.
3.4. Donepezil, β- and γ-secretase modulators and Aβ immunotherapies for cognitive decline Donepezil is an acetylcholinesterase inhibitor currently used to improve neurobehavioral symptoms
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for elderly patients with AD by enhancing the cholinergic transmission (Birks and Harvey, 2003). This drug has been shown to be effective and safe in adults with DS for AD-like dementia,
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improving global and specific mental functions of DS patients with severe cognitive impairment, as demonstrated in a randomized, double blind, placebo-controlled trial (Kondoh et al., 2011). Recently, it has been reported in the case of an adolescent with severe behavioural disturbances for
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which donepezil treatment resulted in the alleviation of symptoms and total recovery of the patient
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to his previous psychosocial levels (Tamasaki et al., 2016). In an attempt to demonstrate the
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efficacy of donepezil on cognitive improvements in children, a randomized, double-blind, placebo-
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controlled multicentre study has been performed with children with DS aged 10-17. That study
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failed to demonstrate any benefit for donepezil versus placebo although the drug appeared to be well tolerated (Kishnani et al., 2010).
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β- and γ-secretase modulators could be considered good candidate for improvement of cognitive
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decline due to their action in targeting the formation of cytotoxic Aβ. The formation of Aβ takes place following the cleavage of APP through two aspartic proteases such as β-secretase and γ-
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secretase (Birks and Harvey, 2003). APP is cleaved at the β-site by β-secretase and is therefore known as the β-site APP cleaving enzyme 1 (BACE 1) (Vassar et al., 1999). A potential strategy to target Aβ plaques in DS could be inhibition of BACE1. However, the homologous BACE2 protein does not share a relationship in the cleavage of APP in humans (Ballard et al., 2016), but may have some protective effect (Sun et al., 2006). Some preclinical studies have showed evidence that the quantity of amyloid protein in the brain, cerebrospinal fluid and plasma can be reduce by β37
secretase inhibitors (Chen et al., 2015; Ghosh et al., 2012; Netzer et al., 2010). However, some other scientists believe that no inhibitors can decrease the amount of Aβ in the human brain, plasma or cerebrospinal fluid (CSF) (Varghese, 2010).
γ-Secretase is a composed by four dissimilar proteins: nicastrin (Nct), presenilin (PS), presenilin-
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enhancer 2 (Pen-2) and anterior pharynx-defective 1 (Aph-1), that are present in a similar (1:1:1:1) stoichiometry (Sato et al., 2007). γ-Secretase is an aspartyl protease belonging to the intra-
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membrane cleaving protease family (I-CLiPs) which includes rhomboid proteases, signal peptide peptidases, and site- 2 peptidases (Bursavich et al., 2016). Semagacestat and avagacesat are two γsecretase inhibitors (GIs) already used in phase II clinical trials for AD. It was found that
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semagacestat did not improve cognitive decline in AD, and exacerbated functional ability at the
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higher doses (Doody et al., 2013). Moreover, significant adverse GI effects have been previously
A
reported (Coric et al., 2012; Doody et al., 2013). Although the FDA-approved GIs cannot be used as
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therapy in DS due to significant adverse effects, recently Stagni and co-worker tested the GI
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ELND006 in Ts65Dn perinatal period providing the proof of principle of the efficacy of an early inhibition of γ-secretase to improve brain development in DS conditions (Stagni et al., 2017).
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Aβ immunotherapies as a strategy to reduce Aβ overload in the brain by using synthetic peptides or
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monoclonal antibodies, have been developed and currently trialled in AD, and represent a promising approach to modify the course of the disease (Mo et al., 2017). Interestingly, evaluation
A
of a vaccine against Aβ (namely ACI-24) is also under investigation by Rafii MS group in a DS clinical trial (ClinicalTrials.gov Identifier: NCT02738450) with the primary outcome of safety and the secondary outcome of reducing neurobehavioral and neurologic manifestations of AD in adults with DS.
3.5. Coenzyme Q10, metformin and melatonin 38
Coenzyme Q10 (CoQ10) is a crucial cofactor of the inner mitochondrial membrane involved in mitochondrial respiratory chain and free radical scavenging. Numerous studies have highlighted its antioxidant potential in preventing oxidative DNA damage and its other neuroprotective effects (Hernández-Camacho et al., 2018; Negida et al., 2016; Yang et al., 2016). Significantly reduced platelet and lymphocytic CoQ10 content and low plasma levels of CoQ10 have been reported in
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people with DS in paediatric age and was found to have a proportional relationship to the intelligence quotient of DS children (Zaki et al., 2017). CoQ10 treatment showed to lower the
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oxidative stress status in children with DS (Miles et al., 2007), however, in a randomized, phase II clinical trial (ClinicalTrials.gov Identifier: NCT00891917), the authors reported no efficacy regarding the primary outcomes e.g. language skills, expressive language ability, and speech In another randomized double-blinded trial in DS children, prolonged CoQ10
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articulation.
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administration for 20 weeks produced an increase in plasma CoQ10 levels and induced protection
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A
against DNA oxidation by modulating DNA repair mechanisms (Tiano et al., 2012).
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Metformin, an FDA-approved drug used for the treatment of type 2 diabetes, has also been recently proposed as a potential therapeutic strategy in DS. Metformin was shown to promote neurogenesis in rodent and human neural precursors and enhance spatial memory formation in normal adult mice
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(Wang et al., 2012), and has been shown to be a pharmacological activator of PGC-1α with a
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consequent ability to counteract impairment of mitochondrial network and correct mitochondrial dysfunction in fibroblasts with Hsa21 trisomy (Izzo et al., 2017b). However, prior to the clinical
A
translation of metformin as a chronic therapy in DS, the relationship between dosage and effect must be considered, given that the drug has never been used in children.
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone mainly secreted from the pineal gland (Tan et al., 2010). It has a wide range of regulatory and protective effects, such as synchronizing circadian rhythm, protecting against oxidative stress, regulating energy metabolism, 39
modulating the immune system, and postponing the ageing process (Singh and Jadhav, 2014). In a pilot study, the comparison between children with DS and age-matched controls in the melatonin plasma levels, showed a reduction in the plasma concentration of melatonin in people with DS, resulting in an increased oxidative risk for DS children (Uberos et al., 2010). Furthermore, treatment of adult Ts65Dn mice with melatonin induced antioxidant and anti-ageing effects in the
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hippocampus (Parisotto et al., 2016). However, an additional study in the same DS mouse model has shown that pre- and post-natal melatonin administration, induced only a partial rescue of brain
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oxidative stress and cognitive behaviours (Corrales et al., 2017). Recently, the neuroprotective and anti neuro-inflammatory effects of melatonin have been suggested, given its action in modulating mitochondria integrity and function in neurons in aging (Idowu et al., 2017; Reiter et al., 2018). No
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3.6. Naturally-occurring phytochemicals
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studies on the effect and safety of melatonin in DS population have been reported to date.
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Polyphenols are naturally occurring phytochemicals produced as secondary metabolites in plants in
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response to various stress conditions, such as environmental stress or injury. They are mainly present in vegetables, fruits, and cereals (Vacca et al., 2016; Valenti et al., 2017). Consumption of a polyphenol-enriched diet has demonstrated protective effects against a large number of ailments for
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examples cardiovascular diseases, neurodegenerative diseases, carcinomas and diabetes (Fantini et
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al., 2015; Grootaert et al., 2015; Vacca et al., 2016). Evidence are present for polyphenol-mediated modulation of lipid oxidation and signalling pathways regulating mitochondrial functions, redox
A
homeostasis and homocysteine metabolism. In addition, polyphenols modulate activity and expression of important Hsa21 genes involved in DS pathogenesis, such as DYRK1A, RCAN1 and the amyloid precursor protein (APP) as well as miRNAs, such as miR-155 (for refs see (Vacca et al., 2016; Valenti et al., 2018). Therefore, these natural integrators may have potential effects in preventing or managing some DS clinical manifestations. However, the assessment of the dose and
40
effect relationship as strategies adequate to improve bioavailability and delivery are not yet completely established for the translation of polyphenols to the clinical use as therapeutics in DS.
Two polyphenols, EGCG and resveratrol, have been proposed as possible natural diet integrators for the management of DS. EGCG is the major polyphenol present in Camellia sinensisis belonging
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to the flavonoid subclass. Specifically, it is a gallic acid esterified catechin and a potent antioxidant (Banerjee and Chatterjee, 2015; Chowdhury et al., 2016). EGCG has been suggested as a potential
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drug candidate for treatment and management of some clinical features of DS due to its multimodal capability of targeting many signalling pathways responsible for the regulation of neural health and function (Vacca et al., 2016). The most studied action of EGCG in DS is its capacity to inhibit
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DYRK1A (Park et al., 2009; Yin et al., 2017). the hyperactive protein kinase in DS which affects
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many downstream pathways linked to neurogenesis and neuroplasticity (see the paragraph 2.1.1).
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Treatment with EGCG of both Ts65Dn mice and young adults with DS have proved to normalize
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DYRK1A activity and rescue brain plasticity and partially improve some cognitive functions linked
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to memory and learning (De la Torre et al., 2014).
A study by Catuara-Solarz co-workers reported that treatment of environmental enrichment and
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45% EGCG containing green tea extract enhanced the corticohippocampal-dependent learning and
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memory. The cognitive improvements were escorted by rescue of cornu ammonis 1 dendritic spine density and a stabilization of the amount of excitatory and inhibitory synaptic markers in dentate
A
gyrus and cornu ammonis 1 (Catuara-Solarz et al., 2016).
In vitro studies on neurons, fibroblasts and limphoblastoid cell with Hsa21 trisomy have revealed other targets of EGCG beyond DYRK1A. EGCG has been shown to be a potent scavenger of ROS produced by mitochondria and potent regulator of mitochondrial homoeostasis (Schroeder et al., 2009). Other beneficial effects of EGCG include activation of mitochondrial biogenesis and 41
bioenergetics trough the targeting of Sirt1/AMPK/PGC1-α pathways (Sutherland et al., 2005; Valenti et al., 2018, 2016, 2013). Protection against β-amyloid-induced mitochondrial apoptosis (Zhang et al., 2017) and glutamate cytotoxicity (J. Yu et al., 2010) was also found. Modulation of cAMP levels by EGCG has also been reported, and an increase in the activity of cAMP-dependent PKA has been shown to increase the NADH: ubiquinone oxidoreductase subunit S4 (NDUFS4)
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phosphorylation in T21 human cells (Valenti et al., 2013).
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However, some questions should be resolved prior to the introduction of EGCG as dietetic integration in DS. These include elucidating the most appropriate mode of delivery and types of green tea extracts (that are commercially available) instead of pure EGCG, the dose-response
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relationship, and the combination of EGCG with other nutraceuticals in order to improve its
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bioavailability. At this regards some contradicting studies have been reported. For instance, Souchet
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and co-workers evaluated the effect of an EGCG extract namely POL-60, containing a mix of green
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tea polyphenols (27% EGCG, and 42% other catechins, 8 % caffeine and 1% sucrose) in
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mBACtgDyrk1a, a mouse model overexpressing DYRK1A, and in Ts65Dn. POL60 was able to rescue components of glutamatergic and GABAergic pathways in the hippocampus and cortex but not in the cerebellum, and reversed brain molecular alterations that disrupt excitatory/inhibitory
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balance. Moreover, it was also found that components of GABAergic pathway were partially
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rescued by other extracts such as decaffeinated green tea extract containing 45% EGCG (Souchet et
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al., 2015).
However, reports are also available which suggest that even using a pure stabilized EGCG in the concentrations which produced therapeutic effects on skeletal phenotypes failed to improve cognitive phenotypes (Stringer et al., 2015). The authors concluded that reliable effect is dependent on the dosage of EGCG. Another recent study by the same group showed that the inhibitory effect of EGCG on DYK1A kinase activity was tissue-dependent. Additionally, lack of advantageous 42
therapeutic behavioural effects and potentially detrimental skeletal effects of high EGCG dose in Ts65Dn mice accentuated the importance of EGCG dosage identification (Stringer et al., 2017).
It should also consider that administration of EGCG in the neonatal period rescues many trisomyassociated brain alterations. However, neonatal treatment did not elicit durable effects on the
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physiology of the hippocampus in adulthood (Stagni et al., 2016), thus suggesting long-term consumption of this polyphenol as a pharmacological tool in DS. It should be highlight that EGCG
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has been tested in a double-blind phase II clinical trial with young adults with DS (Table 2). The study reported EGCG benefits in potentiating cognitive training and improving visual recognition memory (de la Torre et al., 2016). EGCG treatment in early childhood could further enhance the
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effects on cognitive behaviour. In a case study we demonstrated that 6 month-treatment of a 10-
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years old DS child with a combination of EGCG and fish oil omega-3, which has been shown to
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improve EGCG bioavailability and synergize its effectiveness (Giunta et al., 2010), improves
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mitochondrial functions, attention and concentration and has no adverse effects (Vacca and Valenti,
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2015). Thus, the combination of EGCG with other nutraceutics could enhance its efficacy.
Another interesting polyphenol in DS is trans-resveratrol, which belongs to the stilbenoid class. We
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previously reported that trans-resveratrol improves mitochondrial biogenesis and bioenergetics
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deficits in hippocampal progenitor cells from Ts65Dn mice by targeting PGC-1α/Sirt1/AMPK axis (Valenti et al., 2016). Moreover, trans-resveratrol downregulates chromosome 21-encoded miR-155
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and plays a key role in the regulation of mitochondrial biogenesis (Latruffe et al., 2015; QuinonesLombrana and Blanco, 2015). Therefore, miR-155 normalization through resveratrol could serve as a potential approach for the prevention of mitochondrial biogenesis impairment and other metabolic changes that occur in DS. However, the poor bioavailability of resveratrol raises a question mark for its efficacy in vivo. Trans-resveratrol is indeed poorly absorbed and rapidly metabolized into metabolites (i.e. glucuronide and sulfate derivatives) that are unstable and subject to rapid urinary 43
clearance (Goldberg et al., 2003). The natural glucoside of resveratrol, the polydatin (transresveratrol-3-O-glucoside), a polyphenol belonging to the chemical family of stilbenoids, present in the plant Polygonum cuspidatum, has the capability to easily cross cell membranes by an active mechanism using glucose carriers and is resistant to enzymatic metabolism. During first pass metabolism, the glucose molecule of polydatin is cleaved off by cellular β-glucosidase, converting
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polydatin into trans-resveratrol where it maximizes tissue concentration (Du et al., 2013). Thus, polydatin could have much higher capacity than resveratrol to be used as a natural drug in DS and
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investigations are currently underway in our laboratory to test its efficacy in cells with Hsa21 trisomy and animal models with DS. Indeed, polydatin exhibits many pharmacological activities similar to those reported for resveratrol, including cardioprotection, neuroprotection, antioxidative,
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anti-inflammatory and multiple-organ protection (Ravagnan et al., 2013; Sies, 2010), and has been
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approved by the FDA for human use and tested in preclinical and clinical trials for other diseases
M
A
(Cremon et al., 2017; Gao et al., 2016).
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Other polyphenols, such as hydroxytyrosol, quercetin and curcumin have also been found to play an important antioxidant role and can modulate several signalling pathways regulating mitochondrial function and ROS homeostasis that have been found to be deregulated in DS (Vacca et al., 2016).
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However, studies testing the effects of these natural molecules on people with DS remain nascent.
3.7. Other dietary supplements
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Evidence for the deficiency of some micronutrients such as vitamins, amino acids and enzymes have been widely described in DS. Low glutathione concentrations and irregular folate metabolism have been reported in DS (Salemi et al., 2015). Deficiency of folate and vitamin B12 is considered to represent a significant risk factor for children with DS (Obermann-Borst et al., 2011; Saghazadeh et al., 2017; Sukla et al., 2015). Similar results were obtained in clinical studies of DS population in Egypt and Italy (Licastro et al., 2006; Meguid et al., 2001). Malabsorption of vitamin B12 without 44
proteinuria was also reported in a child with DS (Cartlidge and Curnock, 1986). Folate is a vital B vitamin which is found in meat, fruits, green vegetables, and beans that provide one-carbon molecules for DNA synthesis, and methylation of proteins (Bernstein et al., 2007; Patterson, 2008). The role of the folate pathway in chromosome 21 non-disjunction was first described by James and
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co-workers (James et al., 1999).
It has been hypothesized that folate has the ability to lower homocysteine levels, and a folate rich
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diet may decrease the incidence for having chromosome non-disjunction, the incidence of children with trisomy (Patterson, 2008). However clinical trials in early infancy of children with DS with folinic acid supplementation alone (ClinicalTrials.gov Identifier: NCT00294593) or in combination
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with vitamins and antioxidants (ClinicalTrials.gov Identifier: NCT00378456) failed to improve
A
N
cognitive and psychomotor development (Blehaut et al., 2010; Ellis et al., 2008) (see Table 2).
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Supplementation with α-tocopherol at a dose of 400 IU/day for 4 months in the diets of DS children
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may decrease oxidative DNA damage (Mustafa Nachvak et al., 2014). α-Tocopherol also decreased lipid peroxidation levels in the Ts65Dn mice model and improved hippocampal dentate gyrus hypo cellularity. Early stage supplementation of α-tocopherol has been reported to improve cognitive
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deficits in Ts65Dn mouse model of DS (Shichiri et al., 2011). However, at higher dosage it may
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enhance mortality (Miller et al., 2005).
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In children with DS, normal Mg2+, Ca2+ and Zn2+ levels were found (Józefczuk et al., 2017). However, in another meta-analysis lower blood levels of Ca2+, Zn2+ and selenium was reported (Saghazadeh et al., 2017). Similar results have been reported from a study conducted on 16 DS subjects (Kadrabová et al., 1996). As well, a reduction in vitamin D, which plays an important role for calcium absorption and immune response (Christakos and DeLuca, 2011), has been described in children and adolescents with DS, in particular in the presence of obesity and autoimmune diseases 45
(Stagi et al., 2015). In the case of hypovitaminosis D, the need for cholecalciferol (Vitamin D3) supplementation has been discussed (Stagi et al., 2015).
Significant differences in amino acids levels have also been found in the DS individuals. A decrease in the plasma concentration of serine and an elevation of plasma concentration of lysine was found
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correlated with premature ageing (Mircher et al., 1997). Several neurotransmitter amino acids have been reported to be altered in the brain of people with DS. Glutamate shortfall is observed in the
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hippocampus of DS individuals, and reduced level of GABA is also found in the temporal cortex and hippocampus in patients with neocortical neurofibrillary tangles (Reynolds and Warner, 1988). Glutathione is a potent antioxidant that eliminates free radicals. Studies have revealed that children
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with DS have low levels of glutathione which is mainly due to overexpression of the SOD1 gene
A
N
(Wang et al., 2003).
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Many clinical trials have been conducted in DS population using nutrients as pharmacological
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agents such as zinc, selenium, megavitamin/mineral preparations, vitamin A, vitamin B6 and its precursors, vasopressin, whose results have been previously reviewed (Ani et al., 2000). However, only few randomized trials have been conducted and none of these trials have shown any
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improvement in the clinical outcomes. Nevertheless, analysis of anonymous questionnaires has
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identified inappropriate use of supplementation with antioxidants, vitamins and fatty acids. These nutraceuticals are very often started in the early infancy, and without any objective quantification
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on neurodevelopmental progress, and 20% of which are not monitored by pediatricians for potential adverse effects (Lewanda et al., 2018).
4. Concluding remarks and future prospective Gene mapping and development of numerous models for DS have greatly expanded horizons in understanding anomalous metabolic functions and pathways that mark DS (Table 1). In this review, 46
we have shown a wide picture of how Hsa21 trisomy can lead to alterations of signalling pathways and epigenetic mechanisms as well as impairment of crucial cellular metabolic pathways and bioenergetics. Altogether, these alterations lead to DS neuropathology (Figure 1). Attempts are being made for further elucidation of the underlying pathogenicity of DS, as well as for the
neurological and biochemical pathways present in DS (Figure 2 and Table 2).
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development and testing of drugs from synthetic and natural origin that could target aberrant
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Various potential therapeutic agents that may applicable for DS are already available on the market. For instance, fluoxetine, bumetanide and metformin, already used for other diseases, are not however, currently under clinical investigations for DS, and further experimental work is required
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prior to discovering a safe and effective drug to improve DS-related intellectual disability. Natural
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products and dietary supplements may also be advantageous for the prevention and management of
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neurological disorders associated with DS. Polyphenols such as EGCG and resveratrol are quite
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beneficial for the treatment of symptoms associated with DS given their multi-targets action.
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However, additional clinical evidence is necessary and rigorous studies are required to explore the pharmacokinetics of these natural products before they can be used effectively in the clinic.
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We believe that mitochondria should be crucial pharmacological targets to maintain neural energy
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and redox homeostasis, fundamental for all neurological processes, and suggest that combinations of therapeutic agents may better improve the complex neurobiological alterations in DS. Moreover,
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future clinical trials should be more refined to include specific and objective outcomes to obtain definitive findings on the efficacy of a treatment in DS. On the other hand, it should be considered that differential drug responses might occur in DS population due to disparity in comorbidities associated to DS (Hefti and Blanco, 2017).
47
Apart from pharmacological strategies for the treatment of DS, epigenomic therapies targeting epigenetic marks have gained considerable attraction to ameliorate DS-related phenotypes. Epidrugs such as methyltransferase inhibitors and histone deacetylase inhibitors, are already used to treat cancer (Campbell and Tummino, 2014) and may be useful to target neurological or specific epigenetic pathways in DS (Mentis, 2016). More recently, epigenomic engineering by the CRISPR-
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Cas 9 system for the Hsa21 editing in DS has been proposed as an innovative and future strategy for
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DS treatment (Mentis, 2016).
We would like to conclude this review with a quote from Prof Jerome Lejeune, the scientist that discovered sixty years ago (in the 1959) the genetic cause of DS regarding the prospects of a cure
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for DS: “We will find a way. It is impossible not to. It is a much less difficult intellectual effort than
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Acknowledgments
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5.
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sending a man on the moon”.
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We are particularly grateful to parents of DS children that very kindly contributed to support in part this study in particular to “Associazione A.M.A.R. Down-Onlus”. The authors wish to thank Dr.
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Laura Marra for manuscript editing.
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Legends to the figures
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Figure 1. Diagram of Down syndrome neuropathology. Hsa21 trisomy in the brain leads to alterations in neurotransmission, neurogenesis and synaptic plasticity with consequent impairments in neurodevelopment (see the neurobiological alterations in the sectors of upper part of the scheme). Amyloid pathology together with an increase in oxidative stress and neural cell death leads to neurodegeneration associated with AD-like dementia and early aging in DS (see the sectors of the
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lower part of the scheme).
Figure 2. Therapeutic action of selected drugs to correct some neurobiological alterations in Down syndrome. Presynaptic GABAergic, glutamatergic and serotonergic and cholinergic transmissions in DS are depicted. In DS post synaptic neurons, overexpression of Hsa21 genes (in red) determines impairment of target genes or pathways (red dotted line ---I) possibly removed by 82
the therapeutic actions of the selected drugs which restore the normal functions (back line continue arrows); the red arrows indicate up () or down () regulation of Hsa21-downstream proteins/receptors in DS. Impairment in signalling pathways controlling mitochondrial functions (involving miR155, DYRK1A, RCAN1, RIP140) induces a reduction in mitochondrial ATP production, an increase in ROS formation, and impairment in many ATP-dependent neurological
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processes including synaptic activity and neurogenesis. Molecular targets of bumetanide, memantine, epigallocatechine-3-gallate (EGCG), fluoxetine, donepezil, β- and γ-secretase
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modulators melatonin, metformin, resveratrol, coenzyme Q and folinic acid are indicated with continued line with the same colours of the respective drug; specifically, () indicates activation effects and (___I) indicate inhibition of overexpression/hyperactivity. NMDAR, NMDA receptor;
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SerotoninR, serotonin receptor; AchE, acetylcholine esterase; nAchR, nicotine acetylcholine
N
receptor; P, phosphorylation; Ac, acetylation; NM, nuclear membrane; MOM, mitochondrial outer
A
membrane; IMS, mitochondrial intermembrane space; MIM, mitochondrial inner membrane.
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Respiratory chain complexes: II, complex II; Q, coenzyme Q; III, complex III; c, cytochrome c; IV,
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complex IV.
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Table 1. Mouse and cellular models for Down syndrome studies. The mouse models, e.g. transgenic mice carrying triplication of orthologous Hsa21 regions, as well as cellular systems, cited in this review are reported. Model name
Origin
Endpoint gene region
References
Numbers of orthologous
Transgenic mouse
Dp(16)1Yey
Transgenic mouse
miR155-Zbtb21
Reeves et al., 1995;
100 Hsa21 genes
Xing et al., 2016
Lipi-Zbtb21
Li et al., 2007;
113 Hsa21 genes
Transgenic mouse
Xing et al., 2016 Sago et al., 1998;
70 Hsa21 genes
Xing et al., 2016
Cb1r1-Fam3b
Olson et al., 2004
A
Ts1Rhr
Sod1-Zbtb21
U
Transgenic mouse
N
Ts1Cje
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Ts65Dn
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genes in 3 copies
Transgenic mouse
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Ts1Yah
M
29 Hsa21 genes
Transgenic mouse
CC
EP
Ts2Yah
A
TgDYRK1A
BAC-Tg1
Transgenic mouse
Abcg1-U2af1
Pereira et al., 2009
12 Hsa21 genes Hspa13-App
Brault et al., 2015;
19 Hsa21 genes
Xing et al., 2016
Dyrk1A
Altafaj et al., 2001
1 Hsa21 gene Transgenic mouse
Rcan1
Xing et al., 2013
1 Hsa21 gene Neural progenitor
From Ts65Dn transgenic
cells (NPCs)
mouse
miR155-Zbtb21
Contestabile et al., 2007; Valenti et al., 2016; 2017
100 Hsa21 genes 85
DS-iPSC-derived
Human fibroblasts
Hsa21 trisomy
Hibaoui et al., 2014
Human: foetal and
Hsa21 trisomy
Valenti et al., 2010; 2011
NPCs Skin fibroblasts
children Heart fibroblasts
Human: foetal
Hsa21 trisomy
Izzo et al., 2004
Lymphoblastoids
Human immortalized
Hsa21 trisomy
Valenti et al., 2013; Granese et al., 2013
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lymphocytes: children
86
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Table 2. Main pharmacological interventions in Down syndrome
The main for human use-approved drugs tested in vitro and in vivo in DS, their targets, therapeutic actions and results relevant for DS are reported. In bracket the treatment duration. Abbreviations: o.d., oral dosage; I.P., intraperitoneal injection; I.C., subcutaneous injection, NPCs, neural progenitor cells. ID, ClinicalTrials.gov identification number. Target
Model system/
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Drug
Dose
Ts65Dn mice
0.2 mg/kg/day
transmission
10-16 weeks old
I.P. (10-16 weeks) aberrant
GABAergic
Ts65Dn mice
(RG1662)
transmission
3-4 months old
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PT
Basmisanil
Fluoxetine
Results
References
Improvement of
Deidda et al.,
hippocampal synaptic
2015
action
GABAergic
ED
Bumetanide
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Trial (ClinicalTrials.gov)
Therapeutic
20 mg/kg/day
Reduction of
excitatory
plasticity and enhanced
GABAA signaling
memory
Negative
Rescue of deficient
Martínez-Cué et al.,
neurogenesis and
2013
o.d. (3-4 months) allosteric modulation of α5-
stabilization of
GABAA receptor
GABAergic synapse density
Phase II trial in DS subjects
20-240 mg
No significant
La Roche
12-30 years old
o.d. twice daily
improvement of
statement
(ID: NCT02024789)
(26 weeks)
cognitive deficits in DS
https://ds-
subjects
int.org/node/3547
Serotonergic
Ts65Dn mice
10 mg/kg/day
Inhibition of
Recovery of the
Stagni et al.,
transmission
(45 days old)
I.P., I.C.
serotonin reuptake
synaptic network
2013; Guidi et al.,
Ts65Dn mice (60 days
10 mg/kg/day
Rescue of hippocampal
2013
old)
o.d. daily (8
synaptic plasticity and
Begenesis et al., 87
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Continued
spatial memory
2014
Table 2. Main pharmacological interventions in Down syndrome (Continued)
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Model system/Trial
Therapeutic
Results
References
action
Ts65Dn mice
30 mg/kg/day
Normalization of
Improvement of
Rueda et
transmission
9 months old
o.d. (10-16 weeks)
LTP and
memory, and cognitive
al., 2010;
improvement of
functions
Victorino et
PT CC E A Donepezil
Dose
Glutamatergic
ED
Memantine
Target
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Drug
Cholinergic transmission
cognition
al., 2017
Pilot randomized double
5-10 mg/day
No differences between
Boada et
blinded trial in DS
o.d. (16 weeks)
drug treated and
al., 2012
subjects
placebo group in
18-32 years old
cognitive and adaptive
(ID N°: NCT01112683)
10 mg/day
functions.
Hanney et
Phase II trial in adults DS
o.d. (52 weeks)
Failed efficacy in
al., 2012
subjects
improving living skills
Above 40 years old
or counteracting
(ISRCTN registry ID N°:
memory and cognitive
ISRCTN47562898)
decline
Randomized double-blinded phase II trial in adult with DS Randomized double-blinded
3 mg/day o.d. (24 weeks)
Improvement of AD-like disease symptoms
Improvement overall functioning of DS patients
Improvement of
No differences between
Kondoh et al., 2011
88
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2.5-5.0 mg/day o.d. (10 weeks)
cognition
drug treated and placebo group in cognitive and adaptive functions.
Kishnani et al., 2010
A
phase III trial in children with DS (ID NCT00754052)
Continued
ED
Target
Model system/Trial
γ-Secretase
Amyloid
Ts65Dn mice
inhibitor
pathway
8 weeks old
(DAPT)
A
Metformin
Therapeutic
Results
References
100 mg/kg/day
Reduction of β-
Rescue of spatial
Netzer et al.,
amyloid levels
learning and
2010
memory deficits
Mitochondria
Randomized open trial
4 mg/kg/day
Rescue of reduced
Protective effect in
Tiano et al.,
and redox
in children and young
o.d. (20 months)
CoQ10 plasma
mitigating DNA
2012
homeostasis
DS subjects
levels.
oxidative damage
Activation of
Improvement of
Izzo et al.,
PGC1α signaling
mitochondrial
2017b
pathway.
dysfunction and
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Coenzyme Q
Dose
action
PT
Drug
M
Table 2. Main pharmacological interventions in Down syndrome (Continued)
5-17 years old
Mitochondrial
Cultured fibroblasts
network and
with Has21 trisomy
0.05-0.5 mM
biogenesis
correction of altered mitochondrial network Melatonin
Mitochondria
Ts65Dn mice
0.5 mg/day
Antioxidant action
Attenuation of
Parisotto et 89
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and redox
6-12 months old
and modulation of
oxidative damage
al., 2016;
mitochondrial
and senescence;
Corrales et
integrity and
no improvement of
al., 2017
function
cognitive impairment
A
homeostasis
o.d.
ED
M
Continued
Table 2. Main pharmacological interventions in Down syndrome (Continued) Model system/Trial
Dose
Therapeutic
Results
References
Mitochondrial
Increase in cell
Valenti et
action 20 μM
DYRK1A,
Cultured fibroblasts with
mitochondria,
Has21 trisomy
ROS
energy and
al., 2013;
oxidative stress
Cultured Ts65Dn NPCs
scavenging.
metabolism;
2016; 2017
neurogenesis,
Activation of
decrease in
neurotrasmission
mitochondrial
oxidative stress;
bioenergetics
activation of
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EGCG
Target
PT
Drug
neurogenesis.
Randomized double-
9 mg/kg per day
DYRK1A
Partial improving
de la Torre
blinded phase II trial in
o.d. (12 months)
inhibition
visual recognition
et al., 2016
DS young adults
memory, inhibitory 90
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(aged 16-34 years)
control, and adaptive
(ID N°: NCT01394796).
behavior;
Case study DS child 10
omega-3
year old
cognitive training.
10mg/kg EGCG plus
Activation of
Vacca and
8mg/kg omega-3
mitochondrial
Valenti,
(EPA+DHA)
respiratory
2015
chain
ED
M
A
EGCG and
potentiating effect in
PT
Continued
Table 2. Main pharmacological interventions in Down syndrome (Continued) Target
CC E
Drug
Resveratrol
Mitochondria,
Model system/Trial
Dose
Therapeutic
Results
References
Activation of
Rescue of
Valenti et
PGC1α/AMPK/
mitochondrial
al., 2016
Sirt1 axis
bioenergetics and
action Cultured Ts65Dn NPCs
10 μM
A
miR-155
biogenesis; Improvement of neurogenesis
Folinic acid
Folate
Randomized double-blinded
1 mg /kg per day
Antioxidant;
Improves the
Blehaut et
metabolism,
phase II/II trial in DS
o.d. (12 months)
improve folate
psychomotor
al., 2010 91
I N U SC R
homocysteine
children
pathway
(aged age 3 to 30 months)
in a subgroup of
(ID N°: NCT00294593)
children on thyroxin treatment.
Antioxidant;
Failed efficacy in
Ellis et al.,
blinded trial in DS
mg, Vitamin A 0.9 mg,
improved
improving
2008
children
Vitamin E 100 mg,
folate
cognitive tasks
(aged up to 7 Months)
Vitamin C 50 mg, folinic
metabolism
(ID N°: NCT00378456)
acid 0.1 mg
Randomized double-
vitamins and
metabolism,
minerals
homocysteine
M
A
Folate
o.d. (18 months)
A
CC E
PT
ED
development only
Selenium 10 mg, Zinc 5
Folinic acid
pathway
metabolism
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S0149-7634(18)30802-9 https://doi.org/10.1016/j.neubiorev.2019.01.001 NBR 3313
To appear in: Received date: Revised date: Accepted date:
17 October 2018 2 January 2019 2 January 2019
Please cite this article as: Vacca RA, Bawari S, Valenti D, Tewari D, Fazel Nabavi S, Shirooie S, Sah AN, Volpicella M, Braidy N, Nabavi SM, Down syndrome: neurobiological alterations and therapeutic targets, Neuroscience and Biobehavioral Reviews (2019), https://doi.org/10.1016/j.neubiorev.2019.01.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Down syndrome: neurobiological alterations and therapeutic targets
Rosa Anna Vacca1*, Sweta Bawari2, Daniela Valenti1, Devesh Tewari2, Seyed Fazel Nabavi3, Samira Shirooie4, Archana N. Sah2, Mariateresa Volpicella5, Nady Braidy6, Seyed Mohammad
1
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Nabavi3
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of
2
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Research, Bari, Italy;
Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun University, Nainital,
India;
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran,
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Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Kermanshah University of
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Iran;
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Medical Sciences, Iran;
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy;
6
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Australia.
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*Correspondence at:
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Rosa Anna Vacca, Institute of Biomembranes, Bioenergetics and Molecular Biothecnology, IBIOM-CNR, Via Amendola 165/A, 70126 Bari, Italy;
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e-mail: [email protected]
Highlights Down syndrome is both a neurodevelopment and neurodegenerative disorder Genetic and metabolic alterations involved in Down syndrome neuropathology are discussed Drugs targeting altered genes and metabolic pathways for therapeutic challenge in DS are discussed 1
Abstract Down syndrome (DS) is a genetic disease that occurs due to an aneuploidy of human chromosome 21. Trisomy of chromosome 21 is a primary genetic cause of developmental abnormalities leading to cognitive and learning deficits. Impairments in GABAergic transmission, noradrenergic neuronal
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loss, anomalous glutamatergic transmission and N-methyl-D-aspartate receptor signalling, mitochondrial dysfunction, increased oxidative stress and inflammation, differentially expressed
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microRNAs, increased expression of crucial chromosome 21 genes, and DNA hyper-methylation and hyperactive homocysteine trans-sulfuration pathway, are common incongruities that have been reported in DS and might contribute to cognitive impairment and intellectual disability. This review
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provides an update on metabolic and neurobiological alterations in DS. It also provides an overview
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of the currently available pharmacological therapies that may influence and/or reverse these
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alterations in DS.
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Key words: chromosome 21 trisomy; neurodevelopment disease; neurotransmission; neurogenesis; mitochondrial dysfunction; neurodegeneration
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Abbreviations:
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Aβ, beta-amyloid; AD, Alzheimer’s disease; AMPK, 5' AMP-activated protein kinase; APP, amyloid precursor protein; BAX, BCL2-Associated X Protein; CAT, catalase; CBS, cystathionine
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beta-synthase; CNS, central nervous system; CoQ10, Coenzyme Q10; Drp1, dynamin-related protein 1; DS, Down syndrome; DSCR, Down syndrome critical region; DYRK1A, dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A; EGCG, epigallocatechin-3-gallate; GABA, γaminobutyric acid; GIs, γ-secretase inhibitors; GPCR, G-protein coupled receptor; GPX, glutathione peroxidase; Hsa21, human chromosome 21; iPSCs, induced pluripotent stem cells; LTD, long-term depression; LTP, long-term potentiation; Mecp2, methyl-CpG binding protein 2; 2
miRNAs, microRNAs; Mnf2, mitofusin 2; MRC, mitochondrial respiratory chain; mTOR, mammalian target of rapamycin; NAM, negative allosteric modulator; NFAT, nuclear factor of activated T-cells; NKCC1, Na-K-Clcotransporter 1; NMDA, N-methyl-D- aspartate; NPCs, neural progenitor cells; NRIP1, nuclear receptor interacting protein 1; Opa1, optic atrophy 1; PKA, protein kinase; A; PiB, C-labeled Pittsburgh compound B; RCAN1, regulator of calcineurin 1; RIP140,
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receptor-interacting protein 140; ROS, reactive oxygen species; SOD, superoxide dismutase; TSP-
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1, thrombospondin 1.
Table of Contents 1. Introduction
Down syndrome
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2.1. Impairments in neurogenesis
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2. Alterations in metabolic and signalling pathways critical for the neuropathology of
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2.1.1. Genetic deregulation
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2.1.2. Epigenetic deregulation 2.1.3. Mitochondrial dysfunction 2.2. Impairments in neurotransmission
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2.1.1. GABAergic transmission
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2.1.2. Glutamatergic transmission 2.1.3. Other synaptic transmissions
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2.3. Impairments in neuroplasticity 2.3.1. Astrocyte-mediated synaptic dysfunction 2.4 Neurodegeneration
3. Selected pharmacological interventions and their targets in Down syndrome 3.1.
Bumetanide and Basmisanil RG1662
3.2.
Fluorexetine 3
3.3.
Memantine
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Donepezil and β- and γ-secretase modulators
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Coenzyme Q10, metformin and melatonin
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Naturally occurring phytochemicals
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Other dietary supplements
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4. Concluding remarks and future prospective 5. Acknowledgments
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6. References
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1. Introduction Down syndrome (DS) is a genetic disorder that develops as a consequence of an aneuploidy of human chromosome 21 (Hsa21) (Antonarakis et al., 2004; Letourneau et al., 2014; Opitz and Gilbert-Barness, 1990; Ruparelia et al., 2010). The most frequent form of DS is a result of full Hsa21 trisomy, which is an outcome of the inability of Hsa21 to segregate during meiosis in a
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developing ovum or, to a lesser extent, in sperm, culminating in an extra copy of the entire Hsa21 in all cell types. The mosaic form is rare and occurs in 3-4 % of DS population, in which some cells
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within a single tissue type exhibit a normal karyotype while others exhibit a Hsa21 trisomy (Antonarakis, 2017; Asim et al., 2015; Rachidi and Lopes, 2008; Reeves et al., 2001; Sherman et al., 2007). The occurrence of partial Hsa21 trisomy leading to DS phenotype is extremely rare
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(Pelleri et al., 2016).
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The incidence of DS is estimated to be 1/750-800 live new-borns, but the risk of Hsa21 non-
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disjunction increases with advanced maternal age (Loane et al., 2013; McKenzie et al., 2016;
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Rudolf et al., 2017). Differences in the use of prenatal screening and pregnancy termination have led to a wide variation in live birth prevalence between countries (Morice et al., 2008; Rudolf et al., 2017). A recent epidemiological study on the prevalence of major birth defects in the live birth
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population in the United States between 2004 and 2006 reported that the estimated annual number
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of infants born each year with DS was 5,657 (Kirby, 2017). In Europe, a twenty-year study (19902009) showed that the total number of cases of infants born with DS was about 14,000 or about 700
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per year (Loane et al., 2013). In comparison, approximately 21,000 infants are born with DS in India every year (Verma, 2000; Verma and Bijarnia, 2002). However, a prospective cohort-based study from an Indian tertiary health care centre between 2005 and 2010 reported a higher incidence of mortality (13 %, of which 80.3 % in children less than 2 years of age). These discrepancies may be due to poor family conditions and reporting errors from medical and allied healthcare professionals (Nahar et al., 2013). 5
While trisomy 21, as the genetic cause of DS, was first reported by Lejeune, Gautier and Turpin nearly 60 years ago (Lejeune et al., 1959), there has been a concerted effort to identify the pathogenic mechanism/s through which the trisomy 21 induces the clinical phenotype. Currently,
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the genotype/phenotype correlation in DS remains unclear.
DS is considered the most prominent condition associated with neurodevelopmental abnormalities
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which determine delay or failure in the acquisition of motor skills, speaking and reading with shortterm memory impairment and learning difficulties (for refs see the reviews (Roizen and Patterson, 2003; Sherman et al., 2007). The syndrome is characterized by neuropathological changes occurring
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in the foetal and neonatal life that lead to alterations in brain development. Indeed, the most striking
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hallmarks of DS phenotype are impairments of brain development and intellectual disability, as
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well as craniofacial defects (Kazemi et al., 2016). Additionally, the brains from people with DS
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have structural and functional abnormalities with developmental alterations in morphogenesis, such
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as reduction in brain volume (including cerebral grey and white matter and cerebellum), and histogenesis, including cortical dysgenesis, delayed myelination, lower neuronal density and abnormal synaptic plasticity (Rachidi and Lopes, 2011). Almost all DS population develop in adult
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life neuropathological features leading to early ageing, senile dementia and neurological alterations
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consistent with the Alzheimer’s disease (AD) phenotype, including extracellular plaques and intracellular tangles (Head et al., 2016; Zis and Strydom, 2018). For these reasons, DS is often
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considered a neurodegenerative disorder.
Apart from intellectual disabilities, a wide range of typical traits can be recognized in DS population that are associated with numerous comorbidities with a high phenotypic variation, but occurring with a higher frequency with respect to the euploid population. The most frequent DSassociated diseases are congenital cardiac defects, occurring in almost 50% of babies with DS 6
(Diamandopoulos and Green, 2018). This is followed by acute lymphoblastic leukaemia, occurring in children with DS that are aged less than 5 years old with a frequency of 1/300 and an incidence 40.7 times greater than that in individuals without DS at the same age (Chisholm, 2018). As well, gastro-intestinal diseases such as Hirschprung disease, affects about 2% of babies born with DS and constitutes about 12% of all cases of gastro-intestinal congenital malformations (Asim et al., 2015;
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Holmes, 2014). Other common medical conditions in DS population are otolaryngologic and periodontal diseases, visual impairments, obesity, obstructive sleep apnea, increased susceptibility
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to seizures, and respiratory diseases (Carfì et al., 2014; Pueschel, 1990; Roizen and Patterson, 2003). DS is also correlated with male infertility (Stefanidis et al., 2011). In addition, people with DS are highly vulnerable to auto-inflammatory diseases such as celiac disease, thyroiditis and
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alopecia indicative of a chronic deregulation of the immune system (Sullivan et al., 2017). As well,
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behavioural and psychological problems including attention deficit hyperactivity and autism
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spectrum disorders (Davis et al., 2018; Määttä et al., 2006) in children, and neuropsychiatric
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symptoms in adults, have been reported in people with DS (Dekker et al., 2018).
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The last few decades have seen a tremendous increase in the life expectancy of patients with DS reaching an average age of 60 years (Bittles and Glasson, 2004; Carfì et al., 2014). This reflects the advancement in the field of medical research and simultaneously poses considerable challenges to
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the healthcare system in terms of catering to the plethora of phenotypic characteristics and other life
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threatening comorbidities that accompany DS in adulthood.
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Intellectual disability invariably associated with DS, still remains a major challenge to manage by families and healthcare professionals involved in the care of people with DS. Every DS individual presents cognitive and learning deficits in a degree ranging from mild to severe. For example, in a DS population, analysis of 53 females (mean age of 35 years) and of 76 males (mean age of 29 years) resulted in intellectual disability scores of 19% mild, 30% moderate 33% severe and 18% profound, with a sex difference being females with better cognitive abilities and speech production 7
compared with males (Määttä et al., 2006). Of note, enriched environment and specific educational methods were shown to improve cognitive development and intellectual disability scores and biological response as suggested by results obtained in behavioural studies in both mouse models of DS, and DS children (Engevik et al., 2016; Martínez-Cué et al., 2005). However, adults with DS have a high risk for progressive cognitive decline and loss of acquired abilities (see the review
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(Krinsky-McHale and Silverman, 2013).
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Many theories have been proposed to explain DS-related abnormalities in the central nervous system (CNS), including the gene dosage effect, the amplified developmental instability, and the critical region hypotheses (Krinsky-McHale and Silverman, 2013). However, the case of
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monozygotic twins with trisomy of Hsa21 but with discordant phenotypes (Grynberg et al., 2007),
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and the case of subjects with DS phenotype but carrying a partial 21 trisomy of a very restricted
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region coding for not already known genes (34 kb on distal 21q22) (Pelleri et al., 2016), have
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highlighted the likely involvement of other mechanisms to explain the wide phenotypic variation
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occurring in subjects with DS. For instance, epigenetic histone modification and DNA methylation, as well as microRNA regulation of gene expression have also been proposed to play a causal role in the aetiology of DS (Mentis, 2016). Transcriptome maps of human endothelial progenitor cells with
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Hsa21 trisomy obtained by massive–scale RNA-sequencing analysis have revealed up or down-
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regulation of transcripts outside the Hsa21 (Costa et al., 2011). More recently, a meta-analysis, comparing transcript expression levels and profiles of several human tissues and cells with trisomy
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21 with their corresponding diploid, has confirmed the gene dosage hypothesis with 3:2 DS/normal ratio for Hsa21 genes, and listed genes mapped on other chromosomes differentially expressed (Pelleri et al., 2018). Mitochondrial dysfunction due to impairment of key regulatory processes (see the review Valenti et al., 2018), leading to a lower ATP production and deficits in total brain energy, as well as overproduction of reactive oxygen species (ROS) (Valenti et al., 2017, 2016, 2011, 2010), are also 8
believed to be involved in the pathogenesis of DS and in DS-related cognitive impairment. Free radical species, produced by dysfunctional mitochondria, can induce a progressive accumulation of oxidative damage in mitochondrial DNA, and endogenous defence mechanisms against oxidative stress are known to be impaired in DS (Druzhyna et al., 1998). This can in turn lead to early cellular aging and neurodegeneration. It is well established, that the efficiency of mitochondrial
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bioenergetics and dynamics is fundamental for the neurobiological mechanisms underlying intellectual development (for refs see (Khacho and Slack, 2018; Valenti et al., 2014). Aberrant
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mitochondrial energy metabolism and oxidative stress could result in the increased susceptibility of individuals with DS to a large spectrum of diseases such as AD, cardiomyopathy and autism spectrum disorders (Helguera et al., 2013).
Coskun et al. (2017) tested the hypothesis that
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peripheral cells from elderly subjects with DS show dementia-specific and disease-specific
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metabolic features. Using lymphoblastic-cell-lines derived from individuals with DS and DS-with-
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dementia, the study showed that DS cells exhibited a slower growth rate under minimum feeding
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and reduced expression of the autophagy marker LC3-II. Taken together, these findings underscore
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the close relationship between metabolic dysfunction and impaired autophagy in DS (Coskun et al., 2017).
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Several mouse models have been generated in order to study genotype/phenotype correlations in DS and in particular, neurobiological alterations in DS brain (see Table 1). Ts65Dn was the first viable
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trisomy model (Reeves et al., 1995) and was widely used as a DS animal model given that it recapitulates the main phenotypic feature of DS ((Reeves et al., 1995). This model possesses a
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major portion of mouse chromosome 16 (MMU16) carrying some of Hsa21 orthologues at its distal end translocated to the centromeric region of mouse chromosome 17 (MMU17). However, it should be mentioned that Ts65Dn, as well as other mouse models, is not trisomic for all Hsa21 orthologues, and is also trisomic for a number of non-Hsa21 orthologues. Therefore, the use of transgenic and trans-chromosomic mice as models to study DS are vigorously debated. Therefore, 9
other model systems, such as stem cell models have also been proposed to study alterations in neuronal development that occur in DS. For example, induced pluripotent stem cells (iPSCs), obtained from skin or blood cells can be genetically "reprogrammed" to assume a stem cell-like state via specific differentiation protocols, to first generate neural progenitor cells (NPCs), and then human neurons in vitro (Scudellari, 2016). These cells are considered an important tool to
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recapitulate neurodevelopmental stages (Hibaoui et al., 2014) or to reproduce early stages of AD
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type pathology in DS (Dashinimaev et al., 2017).
In this review we report an overview of selected preclinical and clinical studies on both mouse models of DS and humans. A comprehensive search for integrative reviews and original research
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articles published up to December 2018 on relevant aspects of neurobiological alterations and
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therapeutic targets in DS using the PubMed/Medline, ISI and clinicaltrials.gov online databases was
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conducted. The current review begins with a description of critical Hsa21 genes and their targets, as
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well as epigenetic DNA and protein modifications that are likely to be involved in DS phenotype.
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We then discuss how alterations in regulatory signalling and metabolic pathways are critically involved in neurobiological abnormalities associated with DS. Finally, the therapeutic efficacy of selected pharmacological strategies, including naturally occurring phytochemicals to attenuate the
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aberrant metabolic pathways associated with DS are also discussed.
2. Alterations in metabolic and signalling pathways critical for the neuropathology of Down
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syndrome
The neuropathogenesis of DS occurs as a result of a combination of several factors leading to alterations in neuronal es including neurogenesis, neurotransmission and neuroplasticity. Mitochondrial dysfunction, oxidative stress and neuroinflammation, altered glucose metabolism, impairment of homocysteine metabolism, and altered proteostasis and secondary messenger
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signalling pathways (Butterfield and Perluigi, 2018), are indicated as possible contributors in the impairments of both CNS formation and degeneration (Figure 1).
2.1. Impairments in neurogenesis During foetal development, neural stem cells proliferate and differentiate into neurons in a process
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called neurogenesis (Kitamura et al., 2009). Notably, in the hippocampus, neurogenesis occurs postnatally and continues throughout life (called adult neurogenesis) as an adaptive response to
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regulate brain plasticity and memory (Spalding et al., 2013). Reduced neurogenesis is considered among the major neurodevelopmental defects leading to cognitive disability in DS. Results obtained using brains of individuals with DS, DS-derived iPSCs, and NPCs from the hippocampus of DS
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mouse models as experimental systems, showed a decline in proliferation potency, impaired
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neuronal maturation, and neural cell death, which occurred concurrently with alterations to
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neurogenesis in DS (Gimeno et al., 2014; Hibaoui et al., 2014). Data obtained from immunostaining
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experiments using cell proliferation protein markers have shown a reduction in proliferation
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potency in the hippocampal dentate gyrus and neocortical germinal matrix in brains of foetuses with DS starting in the early gestational age (17-23 weeks) (Contestabile et al., 2007; Guidi et al., 2008). The dentate gyrus has a key role in cognition and memory acting as a pre-processor of incoming
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information, which is subsequently processed in the granule cells and pyramidal neurons of the
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hippocampal CA3 (Miyata et al., 2017). A reduction in cell proliferation was also shown in vitro both in neurospheres obtained from the frontal cortex of DS foetuses (Lu et al., 2012) and in NPCs
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obtained from the dentate gyrus of the hippocampus of Ts65Dn mouse model (Valenti et al., 2016). The reduced proliferation potency of neural precursor cells in the DS brain is accompanied by impairments in neuro-differentiation. Immunohistochemical quantification of the number of mature neurons (NeuN-positive cells) and astrocytes (GFAP-positive cells) in both the DG of hippocampus of Ts65Dn mice and hippocampal and para-hippocampal regions of foetuses with Hsa21 trisomy, showed a reduction in the number of neurons and an increase in the number of astrocytes with 11
respect to diploidy (Guidi et al., 2008). Consistently, analysis of iPSCs derived from monozygotic twins discordant for trisomy 21 showed that DS iPSCs exhibit a reduced number of neurons and a shift from neuronal to astroglial and oligodendroglial differentiation. Additionally, neurons also displayed reduced length of neurites (Hibaoui et al., 2014). The reduction in both neural proliferation and differentiation in several brain regions indicates that the impairment in
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neurogenesis is an early event in DS.
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Several mechanisms involved in defective neuronal proliferation and differentiation in DS have been evaluated using mouse and cellular models of DS (Stagni et al., 2018). These include overexpression of some Hsa21 gene products, as well as epigenetic alterations. Herein, we report
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evidence supporting also the crucial role played by mitochondrial dysfunction in the deregulation of
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2.1.1. Genetic deregulation
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neurogenesis in DS.
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The ‘gene-dosage effect’ hypothesis i.e. the 1.5-fold increase of Hsa21 genes, due to an extra copy of Hsa21, has been first suggested to be responsible for the metabolic alterations leading neurological and cognitive impairments in people with DS (Delabar et al., 1993). Importantly,
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genes on Hsa21 encode many transcription factors or regulatory proteins that induce a secondary
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genome-wide transcriptional deregulation, resulting in down-or up-regulation of crucial genes on both Hsa21 and other chromosomes involved in impaired neurogenesis in DS (Rachidi and Lopes,
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2011).
The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) is thought to be a crucial Hsa21 gene strongly implicated in various DS phenotypes as demonstrated in TgDYRK1A transgenic mice over-expressing DYRK1A (Altafaj et al., 2001). Indeed, hyperactivity of DYRK1A protein is known to be involved in the derangement of excitatory-inhibitory balance, generation of 12
neurodevelopmental abnormalities and other behavioural phenotypes of DS associated with cognitive deficits (Ruiz-Mejias et al., 2016). DYRK1A is also associated with regulation of synaptic plasticity and memory consolidation. Amplified gene dosage resulted in defects of brain morphogenesis, low levels of BDNF and mnemonic deficits in DS mice (Guedj et al., 2009). Overexpression of DYRK1A has also been found in the brain of foetuses and adults with DS
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(Lockstone et al., 2007) and in DS iPSCs-derived NPCs (Hibaoui et al., 2014). DYRK1A is present in both the nucleus and cytoplasm of mammalian cells (Figure 2), and appears to have a crucial role
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during neurogenesis and CNS development. Genome-wide analysis of DYRK1A-associated loci reveals that in the nucleus this kinase is recruited to proximal promoters of growth-related genes, actively transcribed by RNA polymerase II, involved in different cellular processes such as
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translation, RNA processing and cell cycle (Di Vona et al., 2015). In addition, DYRK1A
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phosphorylates multiple targets in both the nucleus and the cytoplasm, including among others
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cyclin L2 and cycline D1 (both are involved in cell cycle regulation and neurogenesis), α-synuclein
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(presynaptic regulation), dynamin 1 (which regulates the endocytosis and apoptotic signalling),
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APP, Tau (both involved in AD), synaptojanin 1 (for synaptic transmission), and the cAMP response element binding (CREB), (which regulates diverse cellular responses), as extensively reviewed in (Becker et al., 2014; Duchon and Herault, 2016; Stagni et al., 2018). In particular, it has
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been reported that DYRK1A phosphorylates cyclin D1 at Thr286 inducing its degradation, which in
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turn determines alterations in cell cycle and negative regulation of neural progenitor cell proliferation (Nakano-Kobayashi et al., 2017). An increase in the DYRK1A gene dosage also
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induces elongation of both G1 and S phases. This correlated with a transient increase in the population of intermediate progenitor neurons and overall reduction in the total neuronal output of the postnatal brain (Smith and Calegari, 2015). It is well established that DYRK1A also phosphorylates p53, which leads to induction of p53 target genes and impaired G1/G0-S phase transition, resulting in a reduced proliferation (Park et al., 2010).
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Inhibition of DYRK1A activity by the naturally occurring polyphenol, epigallocatechin-3-gallate (EGCG) ameliorated cognitive behavioural phenotypes and excitatory-inhibitory equilibrium in a DS mouse model (de la Torre and Dierssen, 2012; Guedj et al., 2009; Souchet et al., 2015), highlighting the involvement of DYRK1A gene over-dosage in the regulation of neurogenesis and cognitive impairment in DS (Stagni et al., 2015). A synthetic compound 3-(4-fluorophenyl)-5-(3,4which
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a
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derivative
of
3,5-
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dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine,
di(polyhydroxyaryl)-7-azaindole named F-DANDY, has been reported to selectively inhibit
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DYRK1A both in vitro and in vivo (in Ts65Dn mice), improving learning and memory in Ts65Dn mice (Neumann et al., 2018). Leucettine 41, a synthetic congener of Leucettamine B alkaloid derivative, has also been shown to normalize overexpressed DYRK1A in Ts65Dn, Tg(Dyrk1a) and
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Dp1Yey mouse models of DS, by selectively inhibiting DYRK1A, thus improving cognitive
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function (Nguyen et al., 2018). As well, a synthetic compound named ALGERNON (altered
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generation of neurons) was found to inhibit DYRK1A in cultured neural stem cells from Ts65Dn
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mice as well as in vivo in Ts65Dn mice, thereby enhancing proliferation in neural stem cells and
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restoring cognitive function in Ts65Dn mice (Nakano-Kobayashi et al., 2017).
The regulator of calcineurin 1 (RCAN1), also known as DS critical region 1 protein (DSCR1), is an
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endogenous inhibitor of the calcineurin phosphatase and is overexpressed in DS (Fuentes et al.,
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2000). It has been reported to play an important role in DS neurodevelopmental deficits impairing neurotrophin trafficking and inducing alterations in the development of the sympathetic nervous
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system (Patel et al., 2015), in Dp(16)1Yey/+ mice, a mouse model of DS trisomic solely for the human 21q11-q22.3 synthetic region (Table 1) (T. Yu et al., 2010). In TgRCAN1 mice overexpressing the sole RCAN1 gene, the density of dendritic spines on hippocampal pyramidal neurons was reduced and accompanied by a failure to maintain long-term potentiation, strongly suggesting that RCAN1 plays an important role in brain development and its up-regulation likely contributes to the neural deficits associated with DS (Martin et al., 2012). Studies in RCAN1- and 14
DYRK1A–overexpressing mice have shown that DYRK1A, which phosphorylates RCAN1 at Ser112 and Thr192 residues, acts synergistically with RCAN1 to regulate the phosphorylation levels of the Nuclear factor of activated T-cells (NFAT). This transcription factor, after translocation into the nucleus, up-regulates the expression of interleukin 2, with a consequent stimulation of growth and differentiation of T cell response (Arron et al., 2006; Jung et al., 2011).
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NFAT also regulates proliferation and differentiation of neural precursor cells; it has been reported that NFAT activation reduces the percentage of cells in G0/1 phase of the cell cycle and causes cell
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cycle elongation (Serrano-Pérez et al., 2015). Altogether these studies have suggested an important role of DYRK1A/RCAN1/NFAT signalling pathways in the regulation of NPC proliferation (Stagni
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et al., 2018).
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Less studied regarding deficit of neurogenesis in DS is the Hsa21-encoded receptor-interacting
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protein 140 (RIP140), whose murine orthologous protein is named nuclear receptor interacting
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protein 1 (NRIP1). NRIP1, through the interaction of nuclear receptor factors, regulates gene
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expression and controls several metabolic processes in mouse (Fritah et al., 2010). Increased expression of the RIP140 protein has been demonstrated in human hippocampus of people with DS exhibiting strong cognitive disabilities (Gardiner, 2006). Knock-out of NRIP1 in mice results in
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learning and memory deficits, as well as an increased stress response, suggesting an involvement of
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this Hsa21 gene in cognitive function (Duclot et al., 2012). Recently Zhao and co-workers have reported that RIP140 participates in the differentiation of stem cells into neuronal progenitor cells
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through a mechanism mediated by the ERK1/2 pathway (Zhao et al., 2017). Thus, ERK1/2 signalling may provide the molecular basis by which RIP140 participates in neural differentiation.
Cystathionine beta synthase (CBS) is another Hsa21-encoded crucial enzyme that might be involved in altered neurogenesis in DS. It is involved in homocysteine metabolism (Chen et al., 2010). Homocysteine is a mediator of two crucial biochemical processes; activated methyl cycle, 15
and trans-sulfuration pathway (Medina et al., 2001). Its significance can be deduced from the fact that alterations in homocysteine levels is implicated in various diseases including neurological disorders (Blom and Smulders, 2011; Miller, 2003; Schalinske and Smazal, 2012), AD (Chen et al., 2010), and congenital abnormalities, such as neural tube defects, cleft palate and congenital heart
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disease (Blom and Smulders, 2011; Škovierová et al., 2016).
Numerous studies have reported significantly diminished plasma homocysteine levels in individuals
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with DS due to excessive CBS-mediated hyperactivity of homocysteine trans-sulfuration pathway (Gane, B and Bhat, V, 2014; Obeid et al., 2012; Pogribna et al., 2001). The hyperactive transsulfuration pathway also accounts for a decline in tetrahydrofolate generation from 5-
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methyltetrahydrofolate resulting in a deficit of functional folate, which is indispensable for de novo
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synthesis of RNA and DNA (Gane, B and Bhat, V, 2014; Pogribna et al., 2001; Song et al., 2015).
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Interestingly, another study showed how CBS impairment plays a crucial role in both
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neurodevelopmental abnormalities and early neurodegeneration in DS. In that study, analysis of
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CBS-positive neurons and astrocytes in cerebelli from foetuses and adults with DS showed a high level of CBS in granular cell layers during foetal development which correlated to an abnormal number of inhibitory neurons; increased CBS in the adult DS brain have been related to AD-like
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dementia (Kanaumi et al., 2006). A study carried out on Ts1Yah mouse model to evaluate the effect
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on DS etiology of the trisomy of genes located in a subtelomeric portion of Hsa21 (namely Abcg1– U2af1), containing CBS, reported that overexpression of the hippocampal CBS gene was associated
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with improved spatial memory and enhanced long term potentiation (Pereira et al., 2009). Another study, carried out on Ms2Yah mouse model to determine the effect of the monosomy of the genes in the same Abcg1-U2af1 region, reported more improved effects on long-term potentiation and memory (Sahun et al., 2014).
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As well, several microRNA (miRNA) are also overexpressed in some brain regions in people with DS and are proposed to contribute to neurodevelopmental deficits. It is well established that miRNAs are 18-24 nucleotide long non-coding RNAs and post-transcriptional regulators of gene expression acting by either destabilizing mRNAs or by repressing translation, thus regulating various physiological processes, such as development, proliferation, differentiation and apoptosis
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(Cannell et al., 2008; Catalanotto et al., 2016; Kamhieh-Milz et al., 2014). Hsa21 harbours at least 29 miRNAs, but only five, namely miR-99a, let-7c, miR-125b-2, miR-155, and miR-802 have been
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thoroughly studied and found implicated in DS pathogenesis, as reviewed in (Brás et al., 2018; Mentis, 2016; Sanchez-Mut et al., 2016). Interestingly, miR-155 and miR-802 directly downregulate the epigenetic modulator methyl-CpG binding protein 2 (Mecp2) (Bofill-De Ros et al.,
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2015), and are implicated in another neurodevelopmental disorder, known as Rett syndrome (De
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Filippis et al., 2015; Liyanage and Rastegar, 2014). Overexpression of miR-155 in the brain of
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people with DS also results in the down-regulation of SNX27, a key regulatory protein assuring the
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glutamate receptor recycling whose loss contributes to synaptic dysfunction in DS (Wang et al.,
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2013). Similarly, differentially expressed miRNAs, specifically miR-138 along with its target zeste homolog 2 (EZH2), were also reported in DS foetal hippocampus, indicating their role in
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neurological manifestations of DS (Shi et al., 2016).
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2.1.2 Epigenetic deregulation Over-expression of many Hsa21 genes causes dysregulation of some epigenetic mechanisms in DS
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including DNA methylation, histone modification and chromatin remodelling, and are reported to play a crucial role in learning and memory defects in DS (for a comprehensive review see (Dekker et al., 2014). DNA methylation serves as a major epigenetic modulator of gene expression (Crider et al., 2012; Moore et al., 2013). Incongruity in DNA methylation is an important causal factor in the development of neural tube defects (Blom and Smulders, 2011; Škovierová et al., 2016), and neurological (Moore et al., 2013) disorders. DNA methylation influences multiple aspects of 17
neurogenesis from stem cell maintenance and proliferation, followed by neuronal differentiation and maturation, and synaptogenesis; mutations in proteins involved in the establishment, maintenance and removal of DNA methylation impact brain development and functions (Jobe and Zhao, 2017).
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Anomalous DNA methylation is a common occurrence in trisomy 21. Hyper-methylation of DNA is association with upregulation of DNA methyltransferase (DNMT) genes DNMT3B and DNMT3L
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and downregulation of TET2 and TET3 demethylation genes have also been reported from a study using skin fibroblasts isolated from DS monozygotic twins (Sailani et al., 2015). Several other genes such as TCF7, SH3BP2, CD3Z, NOD2 TMEM131, EIF4E, SUMO3, CPT1B, NPDC1 and
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PLD6 from blood-derived leukocytes and T-lymphocytes of DS individuals exhibited differential
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methylation (Kerkel et al., 2010). Jin and co-workers proposed a role of epigenetic mechanisms in
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the plethora of phenotypic outcomes of trisomy 21. They also showed the presence of global DNA
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hyper-methylation in placental villi cells of DS foetuses and leukocytes from DS adults (Jin et al.,
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2013). Hyper-methylated lymphocytic DNA has also been reported in children with DS (Pogribna et al., 2001). As previously discussed, it should be highlighted that repression of the demethylase Mecp2, secondary to trisomic overexpression of Hsa21-derived miRNAs miR-155 and miR802
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(Bofill-De Ros et al., 2015), may partly contribute to the hyper-methylation and neurochemical
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alterations observed in the brains of DS individuals. hypo-methylation of mitochondrial DNA has also been reported in DS due to a mitochondrial methyl imbalance linked to a reduction in S-
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adenosyl-methionine synthesis (Infantino et al., 2011).
Histone deacetylation and acetylation are other epigenetic mechanisms influenced by some Hsa21 genes. DYRK1A, for example, activates SIRT1 phosphorylation and promotes histone deacetylation (Guo et al., 2010); on the other hand, DYRK1A interacts with NRSF/REST affecting chromatin re-
18
modeling and deregulates the levels of gene clusters essential for neural differentiation leading to neuronal alterations in DS (Lepagnol-Bestel et al., 2009).
2.1.3. Mitochondrial dysfunction Mitochondrial metabolism strongly influences the distinct developmental steps of adult
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neurogenesis (Beckervordersandforth, 2017). Several recent studies reported that activation of mitochondrial biogenesis and function induces a metabolic shift from glycolysis to oxidative
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phosphorylation, which mediates the cell fate decision to start the neurogenesis process inducing neural stem cells to generate actively proliferating intermediate progenitor cells which differentiate into mature neurons. Disturbances in mitochondrial function and signalling lead to changes in the
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cell fate and negatively affect the neurogenesis and neuroplasticity processes (for refs see the
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reviews Arrázola et al., 2018; Beckervordersandforth, 2017; Khacho et al., 2019).
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In this light, we have already reviewed and discussed how deficits in neural energy due to
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mitochondrial dysfunction is critical for the aetiology of DS (Valenti et al., 2018, 2014). Mitochondrial dysfunction is an early event in DS and is even considered to be responsible for nondisjunctional disabilities of chromosomes during meiosis in embryos that results in aneuploidies
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like DS (Coskun and Busciglio, 2012; Eichenlaub-Ritter et al., 2011; Schon et al., 2000). The
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presence of significantly high ROS and disrupted mitochondrial network has been reported in DS human fibroblasts as well as mouse embryonic fibroblasts (Zamponi et al., 2018).
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Oligonucleotide microarray analysis profiling of the transcriptome of Hsa21 genes of DS foetal hearts showed downregulation of mitochondrial genes specifically those encoding for mitochondrial enzymes (Conti et al., 2007). Similar downregulation of mitochondrial genes along with mitochondrial morphological alterations and respiratory activity aberrations were also observed in DS foetal fibroblasts and neural progenitor cells (Izzo et al., 2017b; Piccoli et al., 2013; Valenti et al., 2017). Accordingly, a recent systematic proteome and proteostasis profiling study in human DS 19
fibroblasts revealed significant downregulation of the mitochondrial proteome, which strongly concurs to the DS phenotype (Liu et al., 2017). However, one study proposed that downregulation of mitochondrial function could be an adaptive mechanism to prevent ROS generation and subsequent cellular damage (Helguera et al., 2013).
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Mitochondrial phenotype in DS is characterized by reduced efficiency to produce ATP through oxidative phosphorylation, decreased respiratory capacity, impaired ability to generate
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mitochondrial membrane potential, as well as alterations in mitochondrial structure and dynamics (see the review (Valenti et al., 2018). The molecular bases for mitochondrial dysfunction and cell energy deficiency in DS have been well studied. An overview of the Hsa21 genes and key
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regulatory signalling pathways involved in mitochondrial dysfunctions in DS have been recently
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reviewed (Izzo et al., 2018; Valenti et al., 2018). In particular, down-regulation of PGC-
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1α/Sirt1/AMPK axis is involved in the impairment of mitochondrial biogenesis (Piccoli et al., 2013;
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Valenti et al., 2016). Alterations to the expression of dynamin-1-like protein (Drp1), mitofusin 2
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(Mnf2) and optic atrophy 1 (Opa1) has been associated with alterations in mitochondrial structure and network (Izzo et al., 2017b; Valenti et al., 2017). In addition, a decrease in cAMP levels and protein kinase A (PKA)-mediated phosphorylation of the mitochondrial respiratory chain (MRC) in
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DS lead to a reduced catalytic efficiency of MRC complex I and ATP synthase with a consequent
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decline in ATP production, reduced cellular energy, an increase in ROS produced by the mitochondria and oxidative stress (Valenti et al., 2011, 2010). Overexpression of RCAN1 in TG
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mice has been shown to promote mitochondrial dysfunction (Wong et al., 2015) and causes DS-like immune dysfunction as shown by Martin and co-workers (Martin et al., 2013). In addition, the miRNAs let-7c and miR-155, have been reported to target genes involved in the regulation of mitochondrial function (Izzo et al., 2017a). Finally, overexpression of the Hsa21-encoded Ets-2 induces translocation of cytochrome c by mitochondria and induction of mitochondrial death pathway leading to degeneration of DS cortical neurons (Helguera, 2005). 20
Repair mechanisms against oxidative stress mediated damage to mitochondrial DNA are also known to be compromised in DS (Druzhyna et al., 1998). Recently, alteration in mitochondrial dynamics and bioenergetics due to deregulation of Drp1 expression and activity has also been shown to impair hippocampal neurogenesis in Ts65Dn mice (Valenti et al., 2017) and the rescue of
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mitochondrial functions restores normal proliferation of NPCs from the hippocampus of Ts65Dn mice (Valenti et al., 2016). This data confirms the hypothesis of Beckervordersandforth that
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mitochondrial metabolism strongly regulates adult neurogenesis (Beckervordersandforth, 2017).
2.2. Impairments in neurotransmission
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The interplay of both inhibitory and excitatory neurotransmitters plays a major role in cognition and
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neurodevelopmental processes (Cohen Kadosh et al., 2015). Derangement in this excitatory-
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inhibitory equilibrium has long been implicated in DS-associated neuronal impairments (Créau,
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2012). Herein we review and discuss the molecular mechanisms of the changes in the main
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neurotransmission processes in DS (see Figure 2).
2.2.1. GABAergic transmission
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The main inhibitory neurotransmitter in humans, γ-aminobutyric acid (GABA), acts by two
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receptors families, GABAARs and GABABRs. GABAARs are ligand-gated chloride channels composed of a combination of several subunit subtypes (Olsen and Sieghart, 2009). GABABR is a
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class of G-protein coupled receptor (GPCR) that associates with a subset of G-proteins controlling specific ion channels (Padgett and Slesinger, 2010) GABABR is composed by three different subunits reported to modulate both synaptic transmission and postsynaptic responses by a direct interaction of Ca2+ and K+ channels, respectively (Pinard et al., 2010).
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In postnatal development or in axonal compartments, GABAAR activation induces membrane depolarization due to a higher intracellular Cl- concentration (Zorrilla de San Martin et al., 2018). In adult neurons, GABAAR becomes hyperpolarized due to a change in the Cl- balance to lower intracellular Cl- concentration and exerts an inhibitory function (see the review (Herbison and Moenter, 2011). Interestingly, recent studies have shown a reversal of function of GABA AR
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signalling in the hippocampus of Ts65Dn mice which was found to be excitatory rather than inhibitory, generated by an inversion in the direction of Cl- currents due to an increase in the
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expression and activity of the Cl- cotransporter NKCC1 (Contestabile et al., 2017; Deidda et al., 2015).
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Numerous studies on GABAergic transmission in DS have been performed in mouse models and in
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Ts65Dn mice where GABA transmission in neurons was found to be increased. Alterations in the
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KCNJ6 gene, which encodes the subunit 2 of the GIRK channel (GIRK2/Kir3.2), and maps to
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Hsa21, provided the first direct association between DS and GABAergic transmission (Hattori et
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al., 2000; Ohira et al., 1997). An extra KCNJ6 copy led to increased mRNA and protein expression of GIRK2 in the hippocampus, cortex and midbrain of Ts65Dn mice (Harashima et al., 2006). Subsequently, GABAB/GIRK currents were shown to increase in cultured primary hippocampal
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neurons (Best et al., 2007), CA1 pyramidal neurons and dentate gyrus granule cells from acute
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slices of the Ts65Dn hippocampus (Best et al., 2012; Kleschevnikov et al., 2012). This increase in neuronal GABAB/GIRK signalling in Ts65Dn mice is likely to enhance GIRK-mediated shunting
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inhibition, and reduces excitatory PSPs, and alter neuronal passive properties which is likely to affect neuronal excitability and plasticity (Koyrakh, 2005; Lüscher et al., 1997).
Similarly, genetic restoration of GIRK2 to disomy in Ts65Dn mice attenuated elevations in GABAB-triggered currents in CA1 pyramidal neurons (Joshi et al., 2016) and dentate gyrus granule cells (Best et al., 2012; Kleschevnikov et al., 2012). 22
Association of GABAergic over-inhibition and cognitive and learning deficits in DS was also demonstrated in a study carried out by Fernandez et al., 2007. The study showed improvement in cognition and long term potentiation (LTP) of Ts65Dn mice on chronic treatment with the GABAA antagonists Picrotoxin (4 weeks) and Pentylenetetrazole (1 year), respectively) (Fernandez et al., 2007). Similar improvements in learning and memory of Ts65Dn mice was also reported following
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administration of selective inverse agonists for α5- GABAA receptor subtype (Braudeau et al., 2011).
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Of note, a discrepancy between the increase in GABA transmission in mouse models and a reduction in GABA concentrations in human foetal brains with DS (Whittle et al., 2007) and in brains of children with DS as measured by magnetic resonance imaging (Śmigielska-Kuzia et al.,
N
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2010) has been previously reported .
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GABAergic dysfunction disrupts the optimal excitatory/inhibitory synaptic balance in DS
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depolarizing GABA transmission and leading to impairments in synaptic plasticity and learning and
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memory deficits in DS (Deidda et al., 2014; Fernandez et al., 2007; Souchet et al., 2015; Zorrilla de San Martin et al., 2018). In line with these findings, enhanced excitability and reduced GABA inhibition has also been reported in cerebellar granule cells from Ts65Dn mice (Das et al., 2013;
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Szemes et al., 2013; Usowicz and Garden, 2012). Treatment with the α5-containing GABAAR
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negative modulator RO4938581, but not bumetanide, ameliorated hyperactivity in Ts65Dn mice (Deidda et al., 2015; Martinez-Cue et al., 2013). This suggests that additional mechanisms apart
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from altered GABA signalling may be associated with the hyperactive phenotypes in Ts65Dn mice. For example, treatment with the GluN2B-selective antagonist Ro25–6981 (Hanson et al., 2013) or EGCG, an inhibitor of the DS triplicated kinase DYRK1A (Xie et al., 2008), the monoacylglycerol lipase inhibitor JZL184 (Lysenko et al., 2014), the neuro-hormone Melatonin (Corrales et al., 2013), the Sonic Hedgehog agonist SAG1.1 (Das et al., 2013), and the selective serotonin reuptake inhibitor fluoxetine (Begenisic et al., 2014; Bianchi et al., 2010; Guidi et al., 2014), have each been 23
shown to restore CA3-CA1 LTP and/or behavioural performances in vulnerable Ts65Dn mice. GABAergic synaptic transmission has also been shown to be modulated by the Akt-mTOR pathway, which has been reported to be hyper-activated in the hippocampus of Ts1Cje mice, a murine model of DS, leading to an increase in local dendritic translation and synaptic plasticity
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impairment (Troca-Marín et al., 2014).
2.2.2. Glutamatergic transmission
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Apart from alterations in GABAergic signalling, anomalous glutamatergic transmission and Nmethyl-D- aspartate receptor (NMDAR) signalling have been reported in the pathobiology of DS. For example, studies have reported delayed development and reduced production of excitatory
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glutamatergic neurons in the cortex of Ts65Dn mice (Chakrabarti et al., 2010, 2007; Guidi et al.,
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2014; Tyler and Haydar, 2013). As well, a lower density of glutamatergic synapses was observed
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using electron microscopy in the cortex and hippocampus of Ts65Dn mice (Ayberk Kurt et al.,
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2004; Chakrabarti et al., 2007; García-Cerro et al., 2014; Guidi et al., 2013; Kurt et al., 2000; Rueda
Weick et al., 2013).
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et al., 2010; Stagni et al., 2013), and in human DS iPSCs-derived neurons (Hibaoui et al., 2014; Despite these findings, electrophysiological studies that investigate the
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involvement of glutamatergic signalling in trisomic mice are nascent in the current literature.
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Impaired glutamatergic transmission has been proposed to account for behavioural disability and learning and memory deficits in both individuals with DS and animal models (Boada et al., 2012;
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Kaur et al., 2014). This has been shown in the Ts2 mouse model for DS, having in triplicate a short Hsa21 region containing APP (Brault et al., 2015), which exhibited a shortage in the levels of glutamate in the hippocampus (Kaur et al., 2014). The reduced glutamate levels resulted in decreased efficiency in nest building, object finding and entering alternate arms of a Y-maze (Kaur et al., 2014). A failure in systemic glutamate uptake, which has been reported to be independent of age has been demonstrated in platelets and fibroblasts from DS individuals (Begni et al., 2003). 24
Deficits in glutamate levels in the hippocampal region (Reynolds and Warner, 1988) and reduction of glutamate, norepinephrine and serotonin levels have also been demonstrated in para-hippocampal gyrus of post-mortem tissue samples from the human DS brain (Risser et al., 1997). This disparity in inherent glutamate uptake in DS is attributed to oxidative stress, as a result of mitochondrial dysfunction, and has also been correlated to Hsa21 gene products and overexpression of the Hsa21-
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encoded proteins APP and superoxide dismutase 1 (SOD1), which are known to further exacerbate
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neurodegeneration and intellectual disability in people with DS (Begni et al., 2003).
2.2.3. Other synaptic transmissions
DS is also associated with progressive noradrenergic neuronal loss in locus coeruleus. Locus
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coeruleus is built by noradrenergic neurons located in the brainstem, in close proximity to the fourth
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ventricle (Aston-Jones et al., 1994). It directs noradrenergic transmission to the majority of brain
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regions involved in cognitive function (Phillips et al., 2016). Noradrenergic loss has been shown to
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propagate cholinergic degeneration, neuroinflammation and memory loss in Ts65Dn mice
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(Lockrow et al., 2011). Restoration of noradrenergic neurotransmission using a prodrug for norepinephrine or a β-adrenergic receptor agonist, reversed cognitive dysfunction in Ts65Dn mouse model of DS (Salehi et al., 2009). Phillips and colleague demonstrated that low levels of
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noradrenaline and impairment of noradrenergic transmission correlated with the occurrence of
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neurodegeneration and dementia in adults with DS. Indeed, detection of low levels of noradrenaline has been found in the cortical and subcortical regions of the postmortem brain of DS people with
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dementia, and in particular, the occurrence of low serum levels of the noradrenaline metabolite 3methoxy-4-hydroxy phenylglycol (MHPG), increased the risk of developing dementia in DS adults by ten-fold (Phillips et al., 2016).
A number of studies have demonstrated disturbances in the cholinergic system in DS, and this may be likely due to alteration in acetylcholine metabolism with possibly significant relationships to 25
AD-like symptoms in DS adult, since impaired acetylcholine metabolism has been reported in the AD brain (Carvajal and Inestrosa, 2011). Reduction in the cholinergic neurotransmitters choline acetyltransferase has also been reported in cortical and sub-cortical regions of DS adult brain tissues when evaluated in frozen post mortem brain tissues of people with DS (Godridge et al., 1987). In Ts65Dn mice, basal forebrain cholinergic neurons degenerate with age and may contribute to
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memory impairments (Chang and Gold, 2008; Granholm et al., 2000). Additionally, choline acetyltransferase activity was increased in the cortex and hippocampus and may likely compensate
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for the reduction in the number of cholinergic neurons (Contestabile et al., 2006).
It has been well established that the serotonergic system is impaired in DS (Bar-Peled et al., 1991;
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Whittle et al., 2007). The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) is central for
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regulation of a wide range of physiological processes in the CNS such as neurogenesis, neuronal
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morphology and synaptogenesis (see the review (Daubert and Condron, 2010), and has been
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implicated in the regulation of mood, cognitive processes and mediating the release of hormones
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(Hoyer et al., 1994). Thirteen diverse 5‐HT receptors have been identified, twelve of which belong to the GPCR superfamily (Van Oekelen et al., 2003). In particular, analysis of the serotonin 5HT1A receptor in DS brains showed that its levels increase during early development but decreases
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below normal levels at the birth (Bar-Peled et al., 1991). In addition, reduced serotonin levels are
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present in the para-hippocampal gyrus and frontal cortical pole of adults with DS (Risser et al., 1997). Given that impaired serotonin uptake can lead to a reduction in the number of neurons in the
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adult brain (Whitaker-Azmitia, 2001), Bianchi and co-authors discussed how alterations in the serotonergic systems, occurring during early life in DS, could contribute to impaired neurogenesis in DS brain and how it may be corrected (Bianchi et al., 2010). London and co-authors suggested that DYRK1A overexpression might be associated with the modification of monoamine neurotransmitters including serotonin; indeed, the transgenic mice for the DYRK1A gene 26
(mBacTGDYRK1A) showed a dramatic reduction of the serotonin contents in several brain areas especially in the hypothalamus (London et al., 2018).
Additionally, a histaminergic deficit has been proposed to contribute to cognitive impairment in DS.
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More specifically, a reduction of histamine-releasing factor (HRF) in the brain of people with DS has been correlated to a decrease in histamine levels associated with cognitive decline and AD-like
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dementia in DS (Kim et al., 2001).
2.3. Impairments in neuroplasticity
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Neuroplasticity is an intrinsic adaptive ability of the nervous system in response to the changing
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milieu, continuous neural activity, learning, and experience (Demarin and Morović, 2014). This
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adaptation can range from functional modulations, such as alterations in neurochemical
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transmission, modulation of dendritic functions, long-term potentiation, or structural adaptations (Demarin and Morović, 2014; Ruge et al., 2012) that include processes from synaptogenesis and
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neurogenesis (Demarin and Morović, 2014; Fuchs and Flügge, 2014) to the revival and reformation of the existing synapses and signalling network (Mundkur, 2005). Basically, neuroplasticity
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accounts for learning and memory, capability of the nervous system and is also responsible for regaining lost abilities of the damaged neuronal system through structural and functional
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rehabilitation (Kleim and Jones, 2008).
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As has been elaborated in this review, DS is a manifestation of abnormalities in neurotransmission, synaptic and neurogenesis impairments. However, neuroplasticity has been also reported to be aberrant in DS (Cramer and Galdzicki, 2012; Dierssen et al., 2003; García-Vallejo et al., 2018; Gardiner et al., 2010). Impaired neuroplasticity in DS is associated with cognitive deficits, and various structural and functional incongruence (Cramer and Galdzicki, 2012), such as impaired 27
dendritic maturation and reduced dendritic length (Takashima et al., 1994), morphological aberration and deficits in the number of dendritic spines (Marin-Padilla, 1976; Purpura, 1975; Suetsugu and Mehraein, 1980; Weitzdoerfer et al., 2001) and reduced synaptic contacts (Rueda et al., 2012). Therefore, improving neuroplasticity seems to be an additional strategy to correcting cognitive impairments in DS. This is because neuroplasticity can reform as well as replenish
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neuronal structures, thus re-establishing the neuronal communication network (García-Vallejo et al.,
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2018; Kays et al., 2012).
Neuronal and synaptic plasticity are known to be modulated by experience-dependent learning. Therefore, experience-dependent cognitive training could prove to be helpful in ameliorating
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cognitive and intellectual disabilities in DS (Bartesaghi et al., 2015). Cognitive training along with
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EGCG treatment has been shown to improve memory and adaptive behaviour in DS subjects in a
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phase II clinical trial (ClinicalTrials.gov Identifier: NCT01699711) (de la Torre et al., 2016). As
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well, providing more spacious and amiable housing conditions to Ts65Dn mice along with EGCG
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treatment improved cognitive functions via increases in dendritic spine density of cornu ammonis 1, and restoration of the balance of inhibitory and excitatory synaptic markers of the cornu ammonis 1
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and dentate gyrus back to normal ranges (Catuara-Solarz et al., 2016).
DYRK1A gene also plays a pivotal role in modulation of brain plasticity and is known to be
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influenced by environmental stimulation through visual-spatial training (Bartesaghi et al., 2015; Pons-Espinal et al., 2013). A study conducted in the year 2009-2010 showed the efficacy of Wii
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gaming technology (that creates virtual reality) in improving sensorimotor functioning in children with DS. Wii gaming aimed at relaying extensive sensorimotor neuronal activity in DS children through mirror mechanism thus targeting experience dependent modulation of neuroplasticity (Wuang et al., 2011).
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Alterations in plasticity have also been observed in various animal models of DS, such as Ts65Dn and Ts1Cje mouse models. In the Ts1Cje mouse model, the trisomic region of MMU16 is translocated to MMU12 rendering it partially trisomic (Davisson, 2005) (Table 1). Both Ts65Dn and Ts1Cje mouse models exhibit abnormality in structure of pyramidal neurons and dendritic spines, as well as impairment of synaptic plasticity. Ts65Dn mice also display impairment of
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experience-dependent neuroplasticity (Dierssen, 2012). The partially trisomic ts1Rhr mouse model (Gupta et al., 2016), displays structural aberrance in dendritic spines and reduced spine density in
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facial dentate. It also exhibits impairment of synaptic plasticity and long-term potentiation in the hippocampus. This mouse model displays morphological aberrations in dendritic spines as well as impairments in neurogenesis. As well, the Kcnj6 transgenic mouse model exhibits functional
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alterations in excitatory synaptic plasticity and long-term depression (Dierssen, 2012). Another
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transgenic mouse model, the DYRK1A bacterial artificial chromosome transgenic mouse model
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(mBACtgDyrk1a) which overexpresses DYRK1A, exhibits enhancement in spine density in the
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pyramidal neurons of prefrontal cortex (Thomazeau et al., 2014). Bidirectional alteration in
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plasticity with impairment in both NMDAR-mediated LTP and endocannabinoid mediated long term depression (LTD) in the hippocampus is also a prominent feature of mBACtgDyrk1a (Ahn et al., 2006; Thomazeau et al., 2014). It also exhibits increases in expression of proteins associated
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with the inhibitory GABAergic pathway and decreases in the expression of proteins of the
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excitatory glutaminergic pathway (Souchet et al., 2014).
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2.3.1. Astrocyte-mediated synaptic dysfunction
Astrocytes play a critical role in the regulation of synaptic plasticity and memory formation (Adamsky and Goshen, 2018; Chung et al., 2015). DS astrocytes have been recognized to have a direct involvement in the reduced synaptic density and abnormal dendritic spine structure and function (Torres et al., 2018). Indeed, during brain development, astrocytes secrete some factors able to induce the formation of functional synapses between neurons (Clarke and Barres, 2013). 29
The astrocyte-neuron interaction is mediated by direct cell-to-cell connection as well as by a complex group of astrocyte-produced molecules, namely “astrocyte secretome” that dynamically changes according to neuronal activity and astrocyte activation (Clarke and Barres, 2013; Kıray et al., 2016). Both neurons and astrocytes in DS show a marked reduction in the thrombospondin 1 (TSP-1) protein expression, an astrocyte-secreted protein having a powerful effect on the
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modulation of both spine number and morphology when evaluated in post mortem foetal brain cell cultures (Garcia et al., 2010; Torres et al., 2018). Depletion of TSP-1 from normal astrocytes
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induced severe changes in spine morphology, while reinstatement of TSP-1 levels rescued the deficit in astrocyte-mediated spine and synaptic morphology. As well, iPSC-derived astrocytes have been shown to have a negative impact on synaptogenesis in DS, due to hyper-activation of the
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mTOR pathway in neurons, and possibly contributing to DS neuropathogenesis (Araujo et al.,
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2.4. Neurodegeneration
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2017).
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Neurodegeneration and the high risk to develop amyloid neuropathology with AD-like symptoms are part of the neurobiological alterations occurring in individuals with DS in adult age. Several neuroimaging researches have long showed that adult DS persons display typical brain alterations
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occurring in AD (Beacher et al., 2009; Lin et al., 2016; Sabbagh et al., 2015; Teipel and Hampel,
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2006). In a study carried out on both AD and DS subjects with dementia, high similarity was reported in the neuropsychological profiles of the two disease groups (Dick et al., 2016). In a recent
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study, evaluation of brain 3D anatomical images and cognitive status of people with DS with an age of 40 years or older revealed a relationship between cognitive deterioration and severity of specific anatomical changes, such as ‘volume reduction in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus’ (Pujol et al., 2018) which indicate early progression of cognitive impairment toward AD in adults with DS. In the next
30
section, we report data that disclose crucial mechanisms and pathways involved in early neurodegeneration in DS.
2.4.1. Amyloid pathway APP gene product encoded by Hsa21 represents a prominent component of the amyloid cascade
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hypothesis of early manifestation of AD in the DS population. APP gene expression in the DS brain was found to be 1.6 fold higher than in the euploid brain and thought to be responsible of the
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accumulation of the plaques containing fibrillar β-amyloid (Aβ) peptide (Lee et al., 2017; Mao et al., 2003). The neurotoxicity of Aβ has been attributed to microglia activation and increased oxidative stress production (Zana et al., 2007). Alteration of the main pathological hallmarks of AD Aβ-containing
plaques,
and
neurofibrillary
tangles
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(including
(NFT)
containing
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hyperphosphorylated tau protein) are similar in DS and AD (Rafii et al., 2015; Tamaoka, 1998;
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Tapiola et al., 2001). Aβ appears to have a similar pattern in DS and sporadic AD and the C-labeled
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Pittsburgh compound B (PiB), used to image Aβ plaques in the brains, showing early striatal
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binding, which is similar to that observed in familial AD. Similarly, tangles appear to occur early in the hippocampus in DS as well in AD (see the review (Head et al., 2016). Production of ROS and oxidative stress, as well as energy depletion by mitochondrial dysfunction are involved in
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intracellular accumulation of Aβ and the pathogenesis of neurodegeneration in DS (Busciglio et al.,
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2002; Paola et al., 2000). As well, activation of the mTOR signalling pathway linked to tau hyperphosphorylation and Aβ generation have been recently shown to correlate with APP triplication and
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neurodegeneration in DS (Di Domenico et al., 2018). Interestingly, alterations in protein quality control mechanisms, such as ubiquitin-proteasome and autophagy, are believed to induce accumulation of Aβ peptides and hyper-phosphorylated tau proteins in the DS brain, and has been proposed to be directly or indirectly involved in early neurodegeneration in DS (Di Domenico et al., 2013; Granese et al., 2013; Nabavi et al., 2018).
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2.4.2. Oxidative stress, mitochondrial dysfunction and neural cell death Enhanced production of ROS is an attribute that is evident in DS since the embryonic stage (Busciglio and Yankner, 1995; Perluigi and Butterfield, 2012), resulting in apoptotic neuronal death and intellectual disability (Busciglio and Yankner, 1995). However, there are a number of in vitro and in vivo studies that support a link between the accumulation of oxidative stress and neuronal
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cell death, considering that neurons are particularly vulnerable to damage and neurodegeneration (for refs see (Barone et al., 2017). ROS, which include volatile hydrogen peroxide, superoxide
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anions, and hydroxyl radicals are produced under physiological conditions by aerobic respiration and several catabolic and anabolic processes (Halliwell, 1991). Recently, we discussed how mitochondrial dysfunction, due to Hsa21 gene overexpression-dependent deregulation of signalling
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pathways controlling mitochondrial functions, is central in the etiological mechanisms leading to
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oxidative stress, cognitive decline, early aging and AD-like dementia in DS (Valenti et al., 2018).
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Thus, mitochondrial dysfunction is not only involved in neurodevelopmental impairment (as
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discussed in the paragraph 2.2.3) but also in neurodegenerative processes, leading to cognitive
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decline in DS. The mitochondrial respiratory chain and in particular, complexes I and III, are the major source of production of the superoxide anion, generated by electron leakage during electron transport, that is converted into H2O2 and O2 by the mitochondrial-MnSOD (Raha and Robinson,
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2000). Impaired mitochondrial respiratory chain and disruption in oxidative phosphorylation can
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lead to a decrease in mitochondrial ATP production and an increase in ROS (Alfadda and Sallam,
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2012).
We have previously demonstrated that dysfunctional mitochondrial complex I in DS cells overproduces ROS in DS human skin fibroblast cell lines (Valenti et al., 2011). Under physiological conditions, ROS are quickly removed before they can cause cellular dysfunction. However, DS cells are not able to efficiently scavenge ROS overproduction and consequently are more susceptible to oxidative damage. Indeed, the elevated intracellular levels of ROS in DS have long 32
been proposed to occur as a direct consequence of overexpression of the SOD1, which plays a crucial role in the metabolism of superoxide radicals and scavenging of ROS (Créau, 2012), and whose overexpression has been indicated in the formation and accumulation of oxidative stress in DS (Rodríguez-Sureda et al., 2015). Hydrogen peroxide generated as a result of superoxide radical metabolism by SOD is further converted to water by catalase (CAT) and glutathione peroxidase
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(GPX). Therefore, an imbalance in SOD/GPX and CAT ratio exacerbates cytosolic ROS accumulation (de Haan et al., 1995). An imbalance in SOD/GPX ratio has been reported in all DS
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tissues (Barone et al., 2017; de Haan et al., 1995; Perluigi and Butterfield, 2012).
Alterations to iron metabolism for deregulation of redox homeostasis in DS has also been recently
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proposed (Barone et al., 2017). A redox proteomic analysis of brains of people with DS under the
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age of 40 compared with age-matched controls, revealed accumulation of protein carbonyls (Di
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Domenico et al., 2013), suggesting that both an increase in oxidative stress and reduced clearance
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of oxidized proteins, possibly due to an impairment in proteostasis network (Aivazidis et al., 2017),
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may contribute to early neurodegeneration in DS.
3. Proposed pharmacological intervention and their targets in Down syndrome
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Various pharmacotherapies have been proposed in DS, mainly for improving cognitive behaviour.
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Many drugs that have shown to be effective in mouse models of DS have prompted clinical trials in young adults or children with Hsa21 trisomy. Some clinical studies have reported significant
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adverse effects that have diminished their translational impact or clinical efficacy (de la Torre and Dierssen, 2012). Herein, we will present and discuss drugs already approved for human use and being tested in clinical trials as promising therapeutic strategies for DS (see Figure 2 and Table 2). Their underlying targets and mechanisms of action in relation to DS and potential pitfalls for their use in human, if any, will also be evaluated.
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3.1. Bumetanide and basmisanil (RG1662) The Na-K-Cl cotransporter 1 (NKCC1) has been reported to be upregulated in the hippocampus of Ts65Dn mouse model of DS and considered to be responsible for aberrant GABA AR signalling, which is found to be excitatory rather than inhibitory (see paragraph 2.1.1). This incongruity in GABAAR signalling is believed to be responsible for the impairment of LTP and LTD. LTP and
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LTD are characterized by the strengthening or weakening (respectively) of synaptic efficiency, following specific stimulation protocols and provides information on learning and memory
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efficiency (Contestabile et al., 2017). Bumetanide, NKCC1 inhibitor, capable of reversing GABAAR signalling, has been shown to be beneficial in improving hippocampal synaptic plasticity and enhancing memory in the Ts65Dn mouse model (Contestabile et al., 2017; Deidda et al., 2015).
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Targeting GABA transmission, and in particular Cl- cotransporters seems to be very effective in
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improving cognitive deficits in DS. However, the bumetanide effect is not maintained after the
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treatment is ceased (Deidda et al., 2015), thus presuming a lifelong treatment with this drug.
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Bumetanide is an FDA-approved diuretic drug for the treatment of acute pathologies. A limitation
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for the long-term use of bumetanide to correct cognitive impairment in DS is that chronic consumption of this diuretic could have adverse effects on renal function. RG1662 or Basmisanil is a negative allosteric modulator of α5-GABAAR, developed by Hoffmann-
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La Roche Ltd (RO4938581) (Mohler, 2012; Potier et al., 2014). It was found to be efficacious in
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rescuing cognitive and hippocampal synaptic deficits in the Ts65Dn mouse model (Martinez-Cue et al., 2013). Braudeau and colleagues (2011) reported that α5-selective GABAAR inverse agonists are
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able to restore cognitive function in a DS mouse model. These results assisted the hypothesis that altering the GABAergic-mediated balance between inhibitory and excitatory neurotransmission can competently alleviate cognitive impairments in DS in preclinical models (Braudeau et al., 2011).
Despite the promising results obtained in pre-clinical trials, the phase II multicentre, double blind clinical trial of RG1662 (a derivative of RO4938581) in DS subjects namely CLEMATIS 34
(ClinicalTrials.gov identifier: NCT02024789) did not obtain any significant outcomes to ameliorate cognitive disabilities in DS population as reported by a La Roche statement (from the web site: https://ds-int.org/node/3547).
3.2. Fluoxetine
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Fluoxetine is a selective serotonin reuptake inhibitor generally used as an antidepressant in adults but has also been reported to modulate the immune system (Di Rosso et al., 2016). It has been
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shown to stimulate survival as well as neurogenesis in the dentate gyrus of the Ts65Dn mouse model (Bianchi et al., 2010) and to restore functional connectivity of the synaptic network of the hippocampus in Ts65Dn mice (Stagni et al., 2013). Fluoxetine successfully produced favourable
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morphological changes in dendritic architecture of the granule cells of Ts65Dn mice during the
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earliest phases of development resulting in proper maturation of granule neurons which is
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considered to be a key factor to rescue neurogenesis and neurodevelopmental defects in DS mouse
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model (Guidi et al., 2013). In the granule and subgranular cell layer of dentate gyrus of Ts65Dn
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mice, fluoxetine treatment promoted proliferation and survival of these hippocampal cells, thus resulting in enhanced neurogenesis (Clark et al., 2006). In addition, prolonged oral treatment with fluoxetine in adult Ts65Dn mice has been shown to regularize GABA release, improving the spatial
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memory skills and recovering hippocampal synaptic plasticity (Begenisic et al., 2014). On a
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positive note, treatment with fluoxetine in the perinatal period resulted in long-term improvements on cognitive impairment and prevented early signs of AD-like pathology in adult Ts65Dn mice
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(Stagni et al., 2015). Beneficial effect in neuronal precursor proliferation potency and dendritic development were also reported in 2-day-old Ts65Dn mice (Guidi et al., 2014). Fluoxetine has been proposed as a potential prenatal pharmacotherapy able to improve foetal hippocampal neurogenesis and improper brain formation (Kuehn, 2016). However, many adverse effects have been reported following long-term treatment of this drug (Riediger et al., 2017), which could limit the continual use of fluoxetine during infancy and adolescence. 35
3.3. Memantine Memantine is a non-competitive NMDA receptor antagonist proposed to improve glutamatergic transmission to ameliorate memory, behaviour and cognitive impairment (Costa et al., 2008; Rueda et al., 2010). An increase in brain derived neurotrophic factors has also been reported in the
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hippocampus and frontal cortex of Ts65Dn mice following treatment with memantine (Lockrow et al., 2011). A pharmacokinetic study inTs65Dn mice revealed that memantine can transfer to the
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offspring through placenta and maternal milk (Victorino et al., 2017). The memory enhancing effect of memantine is thought to be a consequence of its NMDA receptor antagonism mediated blocking of excessive calcium influx (Lipton, 2004) which is known to mediate disparities in neuronal
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signalling involved in memory and cognition (Parsons et al., 2007). As well, memantine has been
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shown to alleviate long-term depression in the hippocampus of Ts65Dn mice which has been
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proposed to be another possible mechanism for its memory enhancing effects in DS (Scott-McKean
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and Costa, 2011). Despite the promising outcomes obtained for cognition and memory
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enhancement in DS mouse models, memantine seems to fail to re-capacitate cognition and enhance memory in DS adults. Indeed, after a randomised double-blind placebo-controlled trial with adults (>40 years) with DS, with and without dementia (ISRCTN registry identifier: ISRCTN47562898),
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Hanney and colleagues concluded that there were non-significant differences between treated and
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placebo groups and that memantine, although well-tolerated, is not an effective treatment to correct dementia in DS (Hanney et al., 2012). On the contrary, Boada and colleagues reported beneficial
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effects of memantine on cognition in a pilot randomized double blinded trial with young adult with DS (between the ages of 18 and 32 year (ClinicalTrials.gov identifier: NCT01112683). Although they found no significant differences between the memantine treated and placebo group in paired learning and pattern recognition memory, which were the two main primary outcomes of the trial, they found a significant improvement in the memantine group in one of subset memory outcomes
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and only infrequent and mild adverse events (Boada et al., 2012), suggesting the importance to explore other biochemical biomarkers in future clinical studies with this drug.
3.4. Donepezil, β- and γ-secretase modulators and Aβ immunotherapies for cognitive decline Donepezil is an acetylcholinesterase inhibitor currently used to improve neurobehavioral symptoms
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for elderly patients with AD by enhancing the cholinergic transmission (Birks and Harvey, 2003). This drug has been shown to be effective and safe in adults with DS for AD-like dementia,
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improving global and specific mental functions of DS patients with severe cognitive impairment, as demonstrated in a randomized, double blind, placebo-controlled trial (Kondoh et al., 2011). Recently, it has been reported in the case of an adolescent with severe behavioural disturbances for
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which donepezil treatment resulted in the alleviation of symptoms and total recovery of the patient
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to his previous psychosocial levels (Tamasaki et al., 2016). In an attempt to demonstrate the
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efficacy of donepezil on cognitive improvements in children, a randomized, double-blind, placebo-
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controlled multicentre study has been performed with children with DS aged 10-17. That study
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failed to demonstrate any benefit for donepezil versus placebo although the drug appeared to be well tolerated (Kishnani et al., 2010).
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β- and γ-secretase modulators could be considered good candidate for improvement of cognitive
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decline due to their action in targeting the formation of cytotoxic Aβ. The formation of Aβ takes place following the cleavage of APP through two aspartic proteases such as β-secretase and γ-
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secretase (Birks and Harvey, 2003). APP is cleaved at the β-site by β-secretase and is therefore known as the β-site APP cleaving enzyme 1 (BACE 1) (Vassar et al., 1999). A potential strategy to target Aβ plaques in DS could be inhibition of BACE1. However, the homologous BACE2 protein does not share a relationship in the cleavage of APP in humans (Ballard et al., 2016), but may have some protective effect (Sun et al., 2006). Some preclinical studies have showed evidence that the quantity of amyloid protein in the brain, cerebrospinal fluid and plasma can be reduce by β37
secretase inhibitors (Chen et al., 2015; Ghosh et al., 2012; Netzer et al., 2010). However, some other scientists believe that no inhibitors can decrease the amount of Aβ in the human brain, plasma or cerebrospinal fluid (CSF) (Varghese, 2010).
γ-Secretase is a composed by four dissimilar proteins: nicastrin (Nct), presenilin (PS), presenilin-
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enhancer 2 (Pen-2) and anterior pharynx-defective 1 (Aph-1), that are present in a similar (1:1:1:1) stoichiometry (Sato et al., 2007). γ-Secretase is an aspartyl protease belonging to the intra-
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membrane cleaving protease family (I-CLiPs) which includes rhomboid proteases, signal peptide peptidases, and site- 2 peptidases (Bursavich et al., 2016). Semagacestat and avagacesat are two γsecretase inhibitors (GIs) already used in phase II clinical trials for AD. It was found that
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semagacestat did not improve cognitive decline in AD, and exacerbated functional ability at the
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higher doses (Doody et al., 2013). Moreover, significant adverse GI effects have been previously
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reported (Coric et al., 2012; Doody et al., 2013). Although the FDA-approved GIs cannot be used as
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therapy in DS due to significant adverse effects, recently Stagni and co-worker tested the GI
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ELND006 in Ts65Dn perinatal period providing the proof of principle of the efficacy of an early inhibition of γ-secretase to improve brain development in DS conditions (Stagni et al., 2017).
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Aβ immunotherapies as a strategy to reduce Aβ overload in the brain by using synthetic peptides or
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monoclonal antibodies, have been developed and currently trialled in AD, and represent a promising approach to modify the course of the disease (Mo et al., 2017). Interestingly, evaluation
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of a vaccine against Aβ (namely ACI-24) is also under investigation by Rafii MS group in a DS clinical trial (ClinicalTrials.gov Identifier: NCT02738450) with the primary outcome of safety and the secondary outcome of reducing neurobehavioral and neurologic manifestations of AD in adults with DS.
3.5. Coenzyme Q10, metformin and melatonin 38
Coenzyme Q10 (CoQ10) is a crucial cofactor of the inner mitochondrial membrane involved in mitochondrial respiratory chain and free radical scavenging. Numerous studies have highlighted its antioxidant potential in preventing oxidative DNA damage and its other neuroprotective effects (Hernández-Camacho et al., 2018; Negida et al., 2016; Yang et al., 2016). Significantly reduced platelet and lymphocytic CoQ10 content and low plasma levels of CoQ10 have been reported in
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people with DS in paediatric age and was found to have a proportional relationship to the intelligence quotient of DS children (Zaki et al., 2017). CoQ10 treatment showed to lower the
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oxidative stress status in children with DS (Miles et al., 2007), however, in a randomized, phase II clinical trial (ClinicalTrials.gov Identifier: NCT00891917), the authors reported no efficacy regarding the primary outcomes e.g. language skills, expressive language ability, and speech In another randomized double-blinded trial in DS children, prolonged CoQ10
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articulation.
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administration for 20 weeks produced an increase in plasma CoQ10 levels and induced protection
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against DNA oxidation by modulating DNA repair mechanisms (Tiano et al., 2012).
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Metformin, an FDA-approved drug used for the treatment of type 2 diabetes, has also been recently proposed as a potential therapeutic strategy in DS. Metformin was shown to promote neurogenesis in rodent and human neural precursors and enhance spatial memory formation in normal adult mice
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(Wang et al., 2012), and has been shown to be a pharmacological activator of PGC-1α with a
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consequent ability to counteract impairment of mitochondrial network and correct mitochondrial dysfunction in fibroblasts with Hsa21 trisomy (Izzo et al., 2017b). However, prior to the clinical
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translation of metformin as a chronic therapy in DS, the relationship between dosage and effect must be considered, given that the drug has never been used in children.
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone mainly secreted from the pineal gland (Tan et al., 2010). It has a wide range of regulatory and protective effects, such as synchronizing circadian rhythm, protecting against oxidative stress, regulating energy metabolism, 39
modulating the immune system, and postponing the ageing process (Singh and Jadhav, 2014). In a pilot study, the comparison between children with DS and age-matched controls in the melatonin plasma levels, showed a reduction in the plasma concentration of melatonin in people with DS, resulting in an increased oxidative risk for DS children (Uberos et al., 2010). Furthermore, treatment of adult Ts65Dn mice with melatonin induced antioxidant and anti-ageing effects in the
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hippocampus (Parisotto et al., 2016). However, an additional study in the same DS mouse model has shown that pre- and post-natal melatonin administration, induced only a partial rescue of brain
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oxidative stress and cognitive behaviours (Corrales et al., 2017). Recently, the neuroprotective and anti neuro-inflammatory effects of melatonin have been suggested, given its action in modulating mitochondria integrity and function in neurons in aging (Idowu et al., 2017; Reiter et al., 2018). No
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3.6. Naturally-occurring phytochemicals
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studies on the effect and safety of melatonin in DS population have been reported to date.
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Polyphenols are naturally occurring phytochemicals produced as secondary metabolites in plants in
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response to various stress conditions, such as environmental stress or injury. They are mainly present in vegetables, fruits, and cereals (Vacca et al., 2016; Valenti et al., 2017). Consumption of a polyphenol-enriched diet has demonstrated protective effects against a large number of ailments for
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examples cardiovascular diseases, neurodegenerative diseases, carcinomas and diabetes (Fantini et
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al., 2015; Grootaert et al., 2015; Vacca et al., 2016). Evidence are present for polyphenol-mediated modulation of lipid oxidation and signalling pathways regulating mitochondrial functions, redox
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homeostasis and homocysteine metabolism. In addition, polyphenols modulate activity and expression of important Hsa21 genes involved in DS pathogenesis, such as DYRK1A, RCAN1 and the amyloid precursor protein (APP) as well as miRNAs, such as miR-155 (for refs see (Vacca et al., 2016; Valenti et al., 2018). Therefore, these natural integrators may have potential effects in preventing or managing some DS clinical manifestations. However, the assessment of the dose and
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effect relationship as strategies adequate to improve bioavailability and delivery are not yet completely established for the translation of polyphenols to the clinical use as therapeutics in DS.
Two polyphenols, EGCG and resveratrol, have been proposed as possible natural diet integrators for the management of DS. EGCG is the major polyphenol present in Camellia sinensisis belonging
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to the flavonoid subclass. Specifically, it is a gallic acid esterified catechin and a potent antioxidant (Banerjee and Chatterjee, 2015; Chowdhury et al., 2016). EGCG has been suggested as a potential
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drug candidate for treatment and management of some clinical features of DS due to its multimodal capability of targeting many signalling pathways responsible for the regulation of neural health and function (Vacca et al., 2016). The most studied action of EGCG in DS is its capacity to inhibit
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DYRK1A (Park et al., 2009; Yin et al., 2017). the hyperactive protein kinase in DS which affects
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many downstream pathways linked to neurogenesis and neuroplasticity (see the paragraph 2.1.1).
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Treatment with EGCG of both Ts65Dn mice and young adults with DS have proved to normalize
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DYRK1A activity and rescue brain plasticity and partially improve some cognitive functions linked
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to memory and learning (De la Torre et al., 2014).
A study by Catuara-Solarz co-workers reported that treatment of environmental enrichment and
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45% EGCG containing green tea extract enhanced the corticohippocampal-dependent learning and
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memory. The cognitive improvements were escorted by rescue of cornu ammonis 1 dendritic spine density and a stabilization of the amount of excitatory and inhibitory synaptic markers in dentate
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gyrus and cornu ammonis 1 (Catuara-Solarz et al., 2016).
In vitro studies on neurons, fibroblasts and limphoblastoid cell with Hsa21 trisomy have revealed other targets of EGCG beyond DYRK1A. EGCG has been shown to be a potent scavenger of ROS produced by mitochondria and potent regulator of mitochondrial homoeostasis (Schroeder et al., 2009). Other beneficial effects of EGCG include activation of mitochondrial biogenesis and 41
bioenergetics trough the targeting of Sirt1/AMPK/PGC1-α pathways (Sutherland et al., 2005; Valenti et al., 2018, 2016, 2013). Protection against β-amyloid-induced mitochondrial apoptosis (Zhang et al., 2017) and glutamate cytotoxicity (J. Yu et al., 2010) was also found. Modulation of cAMP levels by EGCG has also been reported, and an increase in the activity of cAMP-dependent PKA has been shown to increase the NADH: ubiquinone oxidoreductase subunit S4 (NDUFS4)
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phosphorylation in T21 human cells (Valenti et al., 2013).
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However, some questions should be resolved prior to the introduction of EGCG as dietetic integration in DS. These include elucidating the most appropriate mode of delivery and types of green tea extracts (that are commercially available) instead of pure EGCG, the dose-response
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relationship, and the combination of EGCG with other nutraceuticals in order to improve its
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bioavailability. At this regards some contradicting studies have been reported. For instance, Souchet
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and co-workers evaluated the effect of an EGCG extract namely POL-60, containing a mix of green
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tea polyphenols (27% EGCG, and 42% other catechins, 8 % caffeine and 1% sucrose) in
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mBACtgDyrk1a, a mouse model overexpressing DYRK1A, and in Ts65Dn. POL60 was able to rescue components of glutamatergic and GABAergic pathways in the hippocampus and cortex but not in the cerebellum, and reversed brain molecular alterations that disrupt excitatory/inhibitory
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balance. Moreover, it was also found that components of GABAergic pathway were partially
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rescued by other extracts such as decaffeinated green tea extract containing 45% EGCG (Souchet et
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al., 2015).
However, reports are also available which suggest that even using a pure stabilized EGCG in the concentrations which produced therapeutic effects on skeletal phenotypes failed to improve cognitive phenotypes (Stringer et al., 2015). The authors concluded that reliable effect is dependent on the dosage of EGCG. Another recent study by the same group showed that the inhibitory effect of EGCG on DYK1A kinase activity was tissue-dependent. Additionally, lack of advantageous 42
therapeutic behavioural effects and potentially detrimental skeletal effects of high EGCG dose in Ts65Dn mice accentuated the importance of EGCG dosage identification (Stringer et al., 2017).
It should also consider that administration of EGCG in the neonatal period rescues many trisomyassociated brain alterations. However, neonatal treatment did not elicit durable effects on the
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physiology of the hippocampus in adulthood (Stagni et al., 2016), thus suggesting long-term consumption of this polyphenol as a pharmacological tool in DS. It should be highlight that EGCG
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has been tested in a double-blind phase II clinical trial with young adults with DS (Table 2). The study reported EGCG benefits in potentiating cognitive training and improving visual recognition memory (de la Torre et al., 2016). EGCG treatment in early childhood could further enhance the
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effects on cognitive behaviour. In a case study we demonstrated that 6 month-treatment of a 10-
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years old DS child with a combination of EGCG and fish oil omega-3, which has been shown to
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improve EGCG bioavailability and synergize its effectiveness (Giunta et al., 2010), improves
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mitochondrial functions, attention and concentration and has no adverse effects (Vacca and Valenti,
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2015). Thus, the combination of EGCG with other nutraceutics could enhance its efficacy.
Another interesting polyphenol in DS is trans-resveratrol, which belongs to the stilbenoid class. We
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previously reported that trans-resveratrol improves mitochondrial biogenesis and bioenergetics
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deficits in hippocampal progenitor cells from Ts65Dn mice by targeting PGC-1α/Sirt1/AMPK axis (Valenti et al., 2016). Moreover, trans-resveratrol downregulates chromosome 21-encoded miR-155
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and plays a key role in the regulation of mitochondrial biogenesis (Latruffe et al., 2015; QuinonesLombrana and Blanco, 2015). Therefore, miR-155 normalization through resveratrol could serve as a potential approach for the prevention of mitochondrial biogenesis impairment and other metabolic changes that occur in DS. However, the poor bioavailability of resveratrol raises a question mark for its efficacy in vivo. Trans-resveratrol is indeed poorly absorbed and rapidly metabolized into metabolites (i.e. glucuronide and sulfate derivatives) that are unstable and subject to rapid urinary 43
clearance (Goldberg et al., 2003). The natural glucoside of resveratrol, the polydatin (transresveratrol-3-O-glucoside), a polyphenol belonging to the chemical family of stilbenoids, present in the plant Polygonum cuspidatum, has the capability to easily cross cell membranes by an active mechanism using glucose carriers and is resistant to enzymatic metabolism. During first pass metabolism, the glucose molecule of polydatin is cleaved off by cellular β-glucosidase, converting
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polydatin into trans-resveratrol where it maximizes tissue concentration (Du et al., 2013). Thus, polydatin could have much higher capacity than resveratrol to be used as a natural drug in DS and
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investigations are currently underway in our laboratory to test its efficacy in cells with Hsa21 trisomy and animal models with DS. Indeed, polydatin exhibits many pharmacological activities similar to those reported for resveratrol, including cardioprotection, neuroprotection, antioxidative,
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anti-inflammatory and multiple-organ protection (Ravagnan et al., 2013; Sies, 2010), and has been
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approved by the FDA for human use and tested in preclinical and clinical trials for other diseases
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(Cremon et al., 2017; Gao et al., 2016).
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Other polyphenols, such as hydroxytyrosol, quercetin and curcumin have also been found to play an important antioxidant role and can modulate several signalling pathways regulating mitochondrial function and ROS homeostasis that have been found to be deregulated in DS (Vacca et al., 2016).
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However, studies testing the effects of these natural molecules on people with DS remain nascent.
3.7. Other dietary supplements
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Evidence for the deficiency of some micronutrients such as vitamins, amino acids and enzymes have been widely described in DS. Low glutathione concentrations and irregular folate metabolism have been reported in DS (Salemi et al., 2015). Deficiency of folate and vitamin B12 is considered to represent a significant risk factor for children with DS (Obermann-Borst et al., 2011; Saghazadeh et al., 2017; Sukla et al., 2015). Similar results were obtained in clinical studies of DS population in Egypt and Italy (Licastro et al., 2006; Meguid et al., 2001). Malabsorption of vitamin B12 without 44
proteinuria was also reported in a child with DS (Cartlidge and Curnock, 1986). Folate is a vital B vitamin which is found in meat, fruits, green vegetables, and beans that provide one-carbon molecules for DNA synthesis, and methylation of proteins (Bernstein et al., 2007; Patterson, 2008). The role of the folate pathway in chromosome 21 non-disjunction was first described by James and
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co-workers (James et al., 1999).
It has been hypothesized that folate has the ability to lower homocysteine levels, and a folate rich
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diet may decrease the incidence for having chromosome non-disjunction, the incidence of children with trisomy (Patterson, 2008). However clinical trials in early infancy of children with DS with folinic acid supplementation alone (ClinicalTrials.gov Identifier: NCT00294593) or in combination
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with vitamins and antioxidants (ClinicalTrials.gov Identifier: NCT00378456) failed to improve
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cognitive and psychomotor development (Blehaut et al., 2010; Ellis et al., 2008) (see Table 2).
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Supplementation with α-tocopherol at a dose of 400 IU/day for 4 months in the diets of DS children
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may decrease oxidative DNA damage (Mustafa Nachvak et al., 2014). α-Tocopherol also decreased lipid peroxidation levels in the Ts65Dn mice model and improved hippocampal dentate gyrus hypo cellularity. Early stage supplementation of α-tocopherol has been reported to improve cognitive
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deficits in Ts65Dn mouse model of DS (Shichiri et al., 2011). However, at higher dosage it may
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enhance mortality (Miller et al., 2005).
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In children with DS, normal Mg2+, Ca2+ and Zn2+ levels were found (Józefczuk et al., 2017). However, in another meta-analysis lower blood levels of Ca2+, Zn2+ and selenium was reported (Saghazadeh et al., 2017). Similar results have been reported from a study conducted on 16 DS subjects (Kadrabová et al., 1996). As well, a reduction in vitamin D, which plays an important role for calcium absorption and immune response (Christakos and DeLuca, 2011), has been described in children and adolescents with DS, in particular in the presence of obesity and autoimmune diseases 45
(Stagi et al., 2015). In the case of hypovitaminosis D, the need for cholecalciferol (Vitamin D3) supplementation has been discussed (Stagi et al., 2015).
Significant differences in amino acids levels have also been found in the DS individuals. A decrease in the plasma concentration of serine and an elevation of plasma concentration of lysine was found
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correlated with premature ageing (Mircher et al., 1997). Several neurotransmitter amino acids have been reported to be altered in the brain of people with DS. Glutamate shortfall is observed in the
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hippocampus of DS individuals, and reduced level of GABA is also found in the temporal cortex and hippocampus in patients with neocortical neurofibrillary tangles (Reynolds and Warner, 1988). Glutathione is a potent antioxidant that eliminates free radicals. Studies have revealed that children
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with DS have low levels of glutathione which is mainly due to overexpression of the SOD1 gene
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(Wang et al., 2003).
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Many clinical trials have been conducted in DS population using nutrients as pharmacological
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agents such as zinc, selenium, megavitamin/mineral preparations, vitamin A, vitamin B6 and its precursors, vasopressin, whose results have been previously reviewed (Ani et al., 2000). However, only few randomized trials have been conducted and none of these trials have shown any
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improvement in the clinical outcomes. Nevertheless, analysis of anonymous questionnaires has
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identified inappropriate use of supplementation with antioxidants, vitamins and fatty acids. These nutraceuticals are very often started in the early infancy, and without any objective quantification
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on neurodevelopmental progress, and 20% of which are not monitored by pediatricians for potential adverse effects (Lewanda et al., 2018).
4. Concluding remarks and future prospective Gene mapping and development of numerous models for DS have greatly expanded horizons in understanding anomalous metabolic functions and pathways that mark DS (Table 1). In this review, 46
we have shown a wide picture of how Hsa21 trisomy can lead to alterations of signalling pathways and epigenetic mechanisms as well as impairment of crucial cellular metabolic pathways and bioenergetics. Altogether, these alterations lead to DS neuropathology (Figure 1). Attempts are being made for further elucidation of the underlying pathogenicity of DS, as well as for the
neurological and biochemical pathways present in DS (Figure 2 and Table 2).
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development and testing of drugs from synthetic and natural origin that could target aberrant
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Various potential therapeutic agents that may applicable for DS are already available on the market. For instance, fluoxetine, bumetanide and metformin, already used for other diseases, are not however, currently under clinical investigations for DS, and further experimental work is required
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prior to discovering a safe and effective drug to improve DS-related intellectual disability. Natural
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products and dietary supplements may also be advantageous for the prevention and management of
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neurological disorders associated with DS. Polyphenols such as EGCG and resveratrol are quite
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beneficial for the treatment of symptoms associated with DS given their multi-targets action.
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However, additional clinical evidence is necessary and rigorous studies are required to explore the pharmacokinetics of these natural products before they can be used effectively in the clinic.
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We believe that mitochondria should be crucial pharmacological targets to maintain neural energy
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and redox homeostasis, fundamental for all neurological processes, and suggest that combinations of therapeutic agents may better improve the complex neurobiological alterations in DS. Moreover,
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future clinical trials should be more refined to include specific and objective outcomes to obtain definitive findings on the efficacy of a treatment in DS. On the other hand, it should be considered that differential drug responses might occur in DS population due to disparity in comorbidities associated to DS (Hefti and Blanco, 2017).
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Apart from pharmacological strategies for the treatment of DS, epigenomic therapies targeting epigenetic marks have gained considerable attraction to ameliorate DS-related phenotypes. Epidrugs such as methyltransferase inhibitors and histone deacetylase inhibitors, are already used to treat cancer (Campbell and Tummino, 2014) and may be useful to target neurological or specific epigenetic pathways in DS (Mentis, 2016). More recently, epigenomic engineering by the CRISPR-
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Cas 9 system for the Hsa21 editing in DS has been proposed as an innovative and future strategy for
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DS treatment (Mentis, 2016).
We would like to conclude this review with a quote from Prof Jerome Lejeune, the scientist that discovered sixty years ago (in the 1959) the genetic cause of DS regarding the prospects of a cure
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for DS: “We will find a way. It is impossible not to. It is a much less difficult intellectual effort than
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Acknowledgments
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5.
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sending a man on the moon”.
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We are particularly grateful to parents of DS children that very kindly contributed to support in part this study in particular to “Associazione A.M.A.R. Down-Onlus”. The authors wish to thank Dr.
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Laura Marra for manuscript editing.
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6. References Adamsky, A., Goshen, I., 2018. Astrocytes in Memory Function: Pioneering Findings and Future Directions. Neuroscience 370, 14–26. https://doi.org/10.1016/j.neuroscience.2017.05.033 Ahn, K.-J., Jeong, H.K., Choi, H.-S., Ryoo, S.-R., Kim, Y.J., Goo, J.-S., Choi, S.-Y., Han, J.-S., Ha, I., Song, W.-J., 2006. DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects. Neurobiology of disease 22, 463–472. https://doi.org/10.1016/j.nbd.2005.12.006
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Aivazidis, S., Coughlan, C.M., Rauniyar, A.K., Jiang, H., Liggett, L.A., Maclean, K.N., Roede, J.R., 2017. The burden of trisomy 21 disrupts the proteostasis network in Down syndrome. PLOS ONE 12, e0176307. https://doi.org/10.1371/journal.pone.0176307
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Alfadda, A.A., Sallam, R.M., 2012. Reactive Oxygen Species in Health and Disease. Journal of Biomedicine and Biotechnology 2012, 1–14. https://doi.org/10.1155/2012/936486
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Legends to the figures
81
Figure 1. Diagram of Down syndrome neuropathology. Hsa21 trisomy in the brain leads to alterations in neurotransmission, neurogenesis and synaptic plasticity with consequent impairments in neurodevelopment (see the neurobiological alterations in the sectors of upper part of the scheme). Amyloid pathology together with an increase in oxidative stress and neural cell death leads to neurodegeneration associated with AD-like dementia and early aging in DS (see the sectors of the
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lower part of the scheme).
Figure 2. Therapeutic action of selected drugs to correct some neurobiological alterations in Down syndrome. Presynaptic GABAergic, glutamatergic and serotonergic and cholinergic transmissions in DS are depicted. In DS post synaptic neurons, overexpression of Hsa21 genes (in red) determines impairment of target genes or pathways (red dotted line ---I) possibly removed by 82
the therapeutic actions of the selected drugs which restore the normal functions (back line continue arrows); the red arrows indicate up () or down () regulation of Hsa21-downstream proteins/receptors in DS. Impairment in signalling pathways controlling mitochondrial functions (involving miR155, DYRK1A, RCAN1, RIP140) induces a reduction in mitochondrial ATP production, an increase in ROS formation, and impairment in many ATP-dependent neurological
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processes including synaptic activity and neurogenesis. Molecular targets of bumetanide, memantine, epigallocatechine-3-gallate (EGCG), fluoxetine, donepezil, β- and γ-secretase
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modulators melatonin, metformin, resveratrol, coenzyme Q and folinic acid are indicated with continued line with the same colours of the respective drug; specifically, () indicates activation effects and (___I) indicate inhibition of overexpression/hyperactivity. NMDAR, NMDA receptor;
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SerotoninR, serotonin receptor; AchE, acetylcholine esterase; nAchR, nicotine acetylcholine
N
receptor; P, phosphorylation; Ac, acetylation; NM, nuclear membrane; MOM, mitochondrial outer
A
membrane; IMS, mitochondrial intermembrane space; MIM, mitochondrial inner membrane.
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Respiratory chain complexes: II, complex II; Q, coenzyme Q; III, complex III; c, cytochrome c; IV,
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complex IV.
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Table 1. Mouse and cellular models for Down syndrome studies. The mouse models, e.g. transgenic mice carrying triplication of orthologous Hsa21 regions, as well as cellular systems, cited in this review are reported. Model name
Origin
Endpoint gene region
References
Numbers of orthologous
Transgenic mouse
Dp(16)1Yey
Transgenic mouse
miR155-Zbtb21
Reeves et al., 1995;
100 Hsa21 genes
Xing et al., 2016
Lipi-Zbtb21
Li et al., 2007;
113 Hsa21 genes
Transgenic mouse
Xing et al., 2016 Sago et al., 1998;
70 Hsa21 genes
Xing et al., 2016
Cb1r1-Fam3b
Olson et al., 2004
A
Ts1Rhr
Sod1-Zbtb21
U
Transgenic mouse
N
Ts1Cje
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Ts65Dn
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genes in 3 copies
Transgenic mouse
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Ts1Yah
M
29 Hsa21 genes
Transgenic mouse
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Ts2Yah
A
TgDYRK1A
BAC-Tg1
Transgenic mouse
Abcg1-U2af1
Pereira et al., 2009
12 Hsa21 genes Hspa13-App
Brault et al., 2015;
19 Hsa21 genes
Xing et al., 2016
Dyrk1A
Altafaj et al., 2001
1 Hsa21 gene Transgenic mouse
Rcan1
Xing et al., 2013
1 Hsa21 gene Neural progenitor
From Ts65Dn transgenic
cells (NPCs)
mouse
miR155-Zbtb21
Contestabile et al., 2007; Valenti et al., 2016; 2017
100 Hsa21 genes 85
DS-iPSC-derived
Human fibroblasts
Hsa21 trisomy
Hibaoui et al., 2014
Human: foetal and
Hsa21 trisomy
Valenti et al., 2010; 2011
NPCs Skin fibroblasts
children Heart fibroblasts
Human: foetal
Hsa21 trisomy
Izzo et al., 2004
Lymphoblastoids
Human immortalized
Hsa21 trisomy
Valenti et al., 2013; Granese et al., 2013
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lymphocytes: children
86
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Table 2. Main pharmacological interventions in Down syndrome
The main for human use-approved drugs tested in vitro and in vivo in DS, their targets, therapeutic actions and results relevant for DS are reported. In bracket the treatment duration. Abbreviations: o.d., oral dosage; I.P., intraperitoneal injection; I.C., subcutaneous injection, NPCs, neural progenitor cells. ID, ClinicalTrials.gov identification number. Target
Model system/
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Drug
Dose
Ts65Dn mice
0.2 mg/kg/day
transmission
10-16 weeks old
I.P. (10-16 weeks) aberrant
GABAergic
Ts65Dn mice
(RG1662)
transmission
3-4 months old
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PT
Basmisanil
Fluoxetine
Results
References
Improvement of
Deidda et al.,
hippocampal synaptic
2015
action
GABAergic
ED
Bumetanide
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Trial (ClinicalTrials.gov)
Therapeutic
20 mg/kg/day
Reduction of
excitatory
plasticity and enhanced
GABAA signaling
memory
Negative
Rescue of deficient
Martínez-Cué et al.,
neurogenesis and
2013
o.d. (3-4 months) allosteric modulation of α5-
stabilization of
GABAA receptor
GABAergic synapse density
Phase II trial in DS subjects
20-240 mg
No significant
La Roche
12-30 years old
o.d. twice daily
improvement of
statement
(ID: NCT02024789)
(26 weeks)
cognitive deficits in DS
https://ds-
subjects
int.org/node/3547
Serotonergic
Ts65Dn mice
10 mg/kg/day
Inhibition of
Recovery of the
Stagni et al.,
transmission
(45 days old)
I.P., I.C.
serotonin reuptake
synaptic network
2013; Guidi et al.,
Ts65Dn mice (60 days
10 mg/kg/day
Rescue of hippocampal
2013
old)
o.d. daily (8
synaptic plasticity and
Begenesis et al., 87
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Continued
spatial memory
2014
Table 2. Main pharmacological interventions in Down syndrome (Continued)
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Model system/Trial
Therapeutic
Results
References
action
Ts65Dn mice
30 mg/kg/day
Normalization of
Improvement of
Rueda et
transmission
9 months old
o.d. (10-16 weeks)
LTP and
memory, and cognitive
al., 2010;
improvement of
functions
Victorino et
PT CC E A Donepezil
Dose
Glutamatergic
ED
Memantine
Target
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Drug
Cholinergic transmission
cognition
al., 2017
Pilot randomized double
5-10 mg/day
No differences between
Boada et
blinded trial in DS
o.d. (16 weeks)
drug treated and
al., 2012
subjects
placebo group in
18-32 years old
cognitive and adaptive
(ID N°: NCT01112683)
10 mg/day
functions.
Hanney et
Phase II trial in adults DS
o.d. (52 weeks)
Failed efficacy in
al., 2012
subjects
improving living skills
Above 40 years old
or counteracting
(ISRCTN registry ID N°:
memory and cognitive
ISRCTN47562898)
decline
Randomized double-blinded phase II trial in adult with DS Randomized double-blinded
3 mg/day o.d. (24 weeks)
Improvement of AD-like disease symptoms
Improvement overall functioning of DS patients
Improvement of
No differences between
Kondoh et al., 2011
88
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2.5-5.0 mg/day o.d. (10 weeks)
cognition
drug treated and placebo group in cognitive and adaptive functions.
Kishnani et al., 2010
A
phase III trial in children with DS (ID NCT00754052)
Continued
ED
Target
Model system/Trial
γ-Secretase
Amyloid
Ts65Dn mice
inhibitor
pathway
8 weeks old
(DAPT)
A
Metformin
Therapeutic
Results
References
100 mg/kg/day
Reduction of β-
Rescue of spatial
Netzer et al.,
amyloid levels
learning and
2010
memory deficits
Mitochondria
Randomized open trial
4 mg/kg/day
Rescue of reduced
Protective effect in
Tiano et al.,
and redox
in children and young
o.d. (20 months)
CoQ10 plasma
mitigating DNA
2012
homeostasis
DS subjects
levels.
oxidative damage
Activation of
Improvement of
Izzo et al.,
PGC1α signaling
mitochondrial
2017b
pathway.
dysfunction and
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Coenzyme Q
Dose
action
PT
Drug
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Table 2. Main pharmacological interventions in Down syndrome (Continued)
5-17 years old
Mitochondrial
Cultured fibroblasts
network and
with Has21 trisomy
0.05-0.5 mM
biogenesis
correction of altered mitochondrial network Melatonin
Mitochondria
Ts65Dn mice
0.5 mg/day
Antioxidant action
Attenuation of
Parisotto et 89
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and redox
6-12 months old
and modulation of
oxidative damage
al., 2016;
mitochondrial
and senescence;
Corrales et
integrity and
no improvement of
al., 2017
function
cognitive impairment
A
homeostasis
o.d.
ED
M
Continued
Table 2. Main pharmacological interventions in Down syndrome (Continued) Model system/Trial
Dose
Therapeutic
Results
References
Mitochondrial
Increase in cell
Valenti et
action 20 μM
DYRK1A,
Cultured fibroblasts with
mitochondria,
Has21 trisomy
ROS
energy and
al., 2013;
oxidative stress
Cultured Ts65Dn NPCs
scavenging.
metabolism;
2016; 2017
neurogenesis,
Activation of
decrease in
neurotrasmission
mitochondrial
oxidative stress;
bioenergetics
activation of
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EGCG
Target
PT
Drug
neurogenesis.
Randomized double-
9 mg/kg per day
DYRK1A
Partial improving
de la Torre
blinded phase II trial in
o.d. (12 months)
inhibition
visual recognition
et al., 2016
DS young adults
memory, inhibitory 90
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(aged 16-34 years)
control, and adaptive
(ID N°: NCT01394796).
behavior;
Case study DS child 10
omega-3
year old
cognitive training.
10mg/kg EGCG plus
Activation of
Vacca and
8mg/kg omega-3
mitochondrial
Valenti,
(EPA+DHA)
respiratory
2015
chain
ED
M
A
EGCG and
potentiating effect in
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Continued
Table 2. Main pharmacological interventions in Down syndrome (Continued) Target
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Drug
Resveratrol
Mitochondria,
Model system/Trial
Dose
Therapeutic
Results
References
Activation of
Rescue of
Valenti et
PGC1α/AMPK/
mitochondrial
al., 2016
Sirt1 axis
bioenergetics and
action Cultured Ts65Dn NPCs
10 μM
A
miR-155
biogenesis; Improvement of neurogenesis
Folinic acid
Folate
Randomized double-blinded
1 mg /kg per day
Antioxidant;
Improves the
Blehaut et
metabolism,
phase II/II trial in DS
o.d. (12 months)
improve folate
psychomotor
al., 2010 91
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homocysteine
children
pathway
(aged age 3 to 30 months)
in a subgroup of
(ID N°: NCT00294593)
children on thyroxin treatment.
Antioxidant;
Failed efficacy in
Ellis et al.,
blinded trial in DS
mg, Vitamin A 0.9 mg,
improved
improving
2008
children
Vitamin E 100 mg,
folate
cognitive tasks
(aged up to 7 Months)
Vitamin C 50 mg, folinic
metabolism
(ID N°: NCT00378456)
acid 0.1 mg
Randomized double-
vitamins and
metabolism,
minerals
homocysteine
M
A
Folate
o.d. (18 months)
A
CC E
PT
ED
development only
Selenium 10 mg, Zinc 5
Folinic acid
pathway
metabolism
92