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Down syndrome: From development to adult life to Alzheimer disease
Author’s Accepted Manuscript Down Syndrome: From Development to Adult Life to Alzheimer Disease D. Allan Butterfield Marzia Perluigi www.elsevier.com
PII: DOI: Reference:
S0891-5849(17)31158-9 https://doi.org/10.1016/j.freeradbiomed.2017.10.374 FRB13491
To appear in: Free Radical Biology and Medicine Cite this article as: D. Allan Butterfield and Marzia Perluigi, Down Syndrome: From Development to Adult Life to Alzheimer Disease, Free Radical Biology and Medicine, https://doi.org/10.1016/j.freeradbiomed.2017.10.374 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 galley proof before it is published in its final citable 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.
EDITORIAL Down Syndrome: From Development to Adult Life to Alzheimer Disease
Down syndrome (DS) is most common genetic cause of intellectual disability resulting from trisomy of the distal part of chromosome 21 (Chr21). Life expectancy for the DS population has significantly improved, although with increasing age pathological dysfunctions are exacerbated and intellectual disability degenerates in most cases to a form of dementia that closely resembles that of Alzheimer disease (AD). Although genetic defects are the crucial determinants of the majority of clinical presentations of the disease such as craniofacial abnormalities, small brain size, accelerated aging, and cognitive decline, other factors play a crucial role in determining the severity of pleiotropic phenotypes. Trisomy 21 is associated with a genetic instability that affects not only Chr21 but also other disomic genes that ultimately results in a wide variability and complex set of clinical features [1, 2]. Brain development and intellectual disabilities are the most striking features of trisomy of Chr21 [3, 4], and language, learning and memory appear to be severely affected [5]. The neuropathology of DS results from the combination of several factors, both genetic and non-genetic, among which oxidative stress, altered glucose metabolism, mTOR activation, mitochondrial dysfunction, altered proteostasis network, including the endosome/lysosome system, are key players and major contributors to neuronal degeneration. The comprehension of degenerative phenomena related to accelerated aging and neurodegeneration is one of the major challenges of research in this field, both at molecular and clinical levels. In the last decades, DS neuropathology has become an attractive field of research to study the contribution of accelerated aging in order to correlate genetic defects to pathological phenotypes and also to understand the role of neurogenesis defects and brain development abnormalities that ultimately results in
1
cognitive decline. Indeed, DS individuals, typically between age of 40-50, show neuropathological hallmarks of Alzheimer disease (AD), including deposition of senile plaques containing amyloid beta-peptide (Aβ), neurofibrillary tangles composed of hyperphoshorylated tau, and cholinergic and serotonergic reduction [6, 7]. AD is virtually inevitable in DS subjects; however, the onset of dementia typically appears in DS adults over the age of 50 years of age, suggesting a quite long prodromal phase in which clinical signs are virtually undetectable (reviewed in [8]). The precise mechanisms by which trisomy 21 lead to the early-onset of AD-like neuropathology and cognitive decline remain to be elucidated. Age-dependent A accumulation provides a significant opportunity for development of targeted clinical trials in people with DS to slow or, ideally, prevent, the onset of AD. Further, progress of sophisticated methodological approaches may allow identification of clinical markers of AD in DS based on plasma and neuroimaging studies. This Special Issue of Free Radical Biology & Medicine aims to provide the scientific community an overall picture of deregulated pathways that are responsible for the main pathological features of the disease, in particular the Alzheimer-like neuropathology, by also discussing putative therapeutic strategies that may slow or attenuate clinical manifestations. The authors of this Special Issue discuss clinical signs and symptoms, pathology, neurogenesis, endosome/lysosomes/exosomes, mitochondrial changes, iron dyshomeostasis and oxidative stress, mTOR activation and downstream sequelae, therapy based on estrogen alterations and use of hormone replacement therapy in women with DS, and finally a mouse model of DS. Specifically, in the section of this Special Issue entitled Clinical, Pathological, and Neurodevelopmental Characteristics of Down Syndrome (DS) and DS with Alzheimer Disease (AD), the paper from Prof. Strydom [9] reviews current knowledge on clinical diagnosis and presentation of dementia in DS in comparison with familial AD (FAD) due to APP mutations and APP duplication. The authors suggest that the clinical presentations in 2
DS are similar to the clinical features associated with APP mutations, known to have an increased Aβ42/ Aβ40 ratio in brain, and highlight the relative lack of vascular complications associated with cerebral amyloid angiopathy in DS in comparison with those rare individuals with AD due to duplication APP. Prof. Busciglio [10] examines the role of astrocytes in dendritic spine alterations and more specifically the involvement of astrocytesecreted thrombospondin-1 (TSP-1) deficits in spine and synaptic neuropathology in DS. He posits that defects in both spine morphology and spine density may underlie alterations in neuronal and synaptic plasticity, ultimately affecting cognitive ability. Prof. Bartesaghi [11] discusses the role of some of the triplicate genes such as DYRK1A, APP, RCAN1 and OLIG1/2, which seem to be critical determinants of neurodevelopmental alterations because they affect both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Furthermore, pathways downstream to these selected genes may represent strategic targets for the design of possible therapeutic interventions. In the section of this Special Issue entitled Brain Cell Biology and Neurodegeneration in DS and DS with AD, Prof. Potier [12] reviews current literature that converge towards the hypothesis that excitatory-inhibitory neurotransmission imbalance occurs in DS, likely early during development. Prof. Potier posits that it is likely learning and memory impairments linked to intellectual disabilities in DS could result from synaptic plasticity deficits and excitatory inhibitory alterations leading to changes in neuronal circuitry in the brain of affected individuals. Prof. Nixon [13] reviews current research on endocytic/lysosomal dysfunction in DS and AD, the role of APP/βCTF in initiating this dysfunction, and the contribution of additional trisomy 21 genes in accelerating endosomal-lysosomal impairment in DS. Collectively, these studies demonstrate that both DS and AD neuropathologies show defects in endocytosis and lysosomal function, appearing at the earliest stages of disease development and progress to widespread failure of intraneuronal waste clearance, neuritic dystrophy and consequent neuronal 3
death. Prof. Mobley [14] discusses the role of intracellular signaling from endosomes in the development and maintenance of the nervous system and how the disruption of this system impacts neurodegeneration in DS. The signaling endosomes represents a well suited system for the transmission of trophic factor signals over long distances from axons and dendrites to the cell bodies of neurons. Changes in endosome structure in DS and AD are present early in these disorders; experimental evidence for disruption of signaling endosome function in other disorders of the nervous system also is reviewed. Prof. Schupf [15] reviews current studies on the role of estrogen-related factors in age at onset and risk for AD in women with DS, a population at high risk for early onset of dementia. The studies are consistent with the notion that early age of menopause and low levels of endogenous bioavailable estradiol in postmenopausal women are associated with earlier age at onset and overall risk for dementia. Accordingly, several studies have shown a protective role for estrogen against AD in DS through a number of biological actions. In the section of this SI entitled Oxidative Stress-related Neurobiology in DS and DS with AD, Prof. Vacca [16] focuses on recent studies demonstrating mitochondrial impairment in DS, focusing on alterations of the molecular pathways controling mitochondrial function. The effects and molecular mechanisms by which naturally occurring and chemically synthetized drugs might exert neuroprotective effects through modulation of mitochondrial function and attenuation of oxidative stress also are discussed. Prof. Perluigi [17] discusses recent findings demonstrating the accumulation of oxidative damage in DS and in particular the specific dysregulation of iron metabolism. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration, but how and to what extent the concerted loss of iron dysheomestasis and increased OS occur in DS is not well understood. New insights are presented. Prof. Butterfield [18] reviews recent research highlighting the complex role of mTOR in age dependent cognitive decline in AD and AD-like dementia in DS. Aberrant mTOR signaling is associated with the 4
presence of two hallmarks of AD pathology, senile plaques and neurofibrillary tangles. Oxidative stress, associated with Chr21-related Aβ and mitochondrial alterations, may contribute to this linkage of mTOR to AD-like neuropathology in DS. In the final section of this Special Issue of FRBM entitled Potential Neuroimaging and Plasma-resident Biomarkers in DS and DS with AD and a Mouse Model Thereof, Prof. Head [19] focuses on the role of Aβ in AD pathogenesis in DS and discusses current approaches for imaging Aβ in vivo. The mechanisms through which Aβ deposits with age, its posttranslational modifications and detection in biofluids also are described. In addition, brain imaging for Aβ, including those by positron emission tomography and ligands that bind Aβ, are summarized in her paper. Prof. Granholm [20] discusses findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS suggesting a close connection between neuroinflammatory pathways, oxidative stress, neural-derived exosomes, and exosome-mediated signaling. The increased neuroinflammatory state observed in people with DS may affect plasma-resident neuronal exosomal AD biomarkers. Moreover, the discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Prof. Dierssen [21] investigates the role of metabolic/inflammatory axis in DS. By using Ts65Dn mice, a validated DS mouse model, for the study of obesity-related inflammatory markers, the authors show that increased adiposity and pro-inflammatory adipokines lead to low-grade inflammation and are important players in the propensity to obesity in DS.
Taken together, the papers in this Special Issue of Free Radical Biology & Medicine on “Down Syndrome: From Development to Adult Life to Alzheimer Disease” provide a comprehensive picture of DS throughout the lifespan. New insights into molecular processes involved in the appearance of cognitive decline, age-dependent progression to 5
AD-like neuropathology and dementia, and potential therapeutic strategies to slow or stop this progression are provided. As the Co-Editors of this Special Issue of FRBM we are pleased to assemble in one locus these important papers. We believe the readers of this Special Issue will learn more of DS and how Chr 21 triplication can provide insights into AD.
6
References [1]
Dierssen, M.; Herault, Y.; Estivill, X. Aneuploidy: from a physiological
mechanism of variance to Down syndrome. Physiol Rev 89:887-920; 2009.
[2]
Antonarakis, S. E.; Lyle, R.; Chrast, R.; Scott, H. S. Differential gene
expression studies to explore the molecular pathophysiology of Down syndrome. Brain Res Brain Res Rev 36:265-274; 2001.
[3]
Devenny, D. A.; Krinsky-McHale, S. J.; Sersen, G.; Silverman, W. P.
Sequence of cognitive decline in dementia in adults with Down's syndrome. J Intellect Disabil Res 44 ( Pt 6):654-665; 2000.
[4]
Devenny, D. A.; Wegiel, J.; Schupf, N.; Jenkins, E.; Zigman, W.; Krinsky-
McHale, S. J.; Silverman, W. P. Dementia of the Alzheimer's type and accelerated aging in Down syndrome. Sci Aging Knowledge Environ 2005:dn1; 2005.
[5] Carlesimo, G. A.; Marotta, L.; Vicari, S. Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down's syndrome. Neuropsychologia 35:71-79; 1997.
[6] Lott, I. T. Neurological phenotypes for Down syndrome across the life span. Prog Brain Res 197:101-121; 2012.
[7]
Wisniewski, H. M.; Rabe, A. Discrepancy between Alzheimer-type
neuropathology and dementia in persons with Down's syndrome. Ann N Y Acad Sci 477:247-260; 1986.
[8] Wiseman, F. K.; Al-Janabi, T.; Hardy, J.; Karmiloff-Smith, A.; Nizetic, D.; Tybulewicz, V. L.; Fisher, E. M.; Strydom, A. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16:564-574; 2015. [9] Zis, P.; Strydom A. Clinical aspects and biomarkers of Alzheimer’s disease in Down syndrome. Free Radic Biol Med, in press; 2017.
7
[10] Torres, M.D.; Garcia, O.; Tang C’ Busciglio, J. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med, in press; 2017.
[11] Stagni, F.; Giacomini, A.; Emili M.; Guidi, S.; Bartesaghi, R. Neurogenesis impairment: an early developmental defect in Down syndrome. Free Radic Biol Med, in press; 2017.
[12] de San Martinm J.Z.; Delabar, J.-M.; Bacci, A.; Potier, M.-C. GABAergic overinhibition, an exciting hypothesis for cognitive deficits in Down syndrome. Free Radic Biol Med, in press; 2017.
[13] Colacurcio, D.J.; Pensalfini, A.; Yiang, Y.; Nixon, R.A. Dysfunction of Autophagy and Endosomal-lysosomal Pathways: Roles in Pathogenesis of Down Syndrome and Alzheimer’s Disease. Free Radic Biol Med, in press; 2017.
[14] Chen, X.-Q.; Sawa, M.; Mobley, W.C. Dysfunction of autophagy and endosomal-lysosomal pathways: roles in pathogenesis of Down syndrome and Alzheimer’s disease. Free Radic Biol Med, in press; 2017.
[15] Schupf, N.; Lee, J.H.; Pang, D.; Zigman, W.B.; Tycko, B.; Sharon KrinskyMcHale, S.; Silverman, W. Epidemiology of Estrogen and Dementia in Women with Down Syndrome. Free Radic Biol Med, in press; 2017.
[16] Valenti, D.; Braidy, N.; De Rasmo, D.; Signorile, A.; Rossi, L.; Atanasov, A.G.; Volpicella, M.; Caude, A.H.; Nabavi, S.M.; Vacca, R.A. Mitochondria as pharmacological targets in Down syndrome. Free Radic Biol Med, in press; 2017.
[17] Barone E.; Arena A.; Head, E.; Butterfield D.A; Perluigi, M. Disturbance of redox homeostasis in Down Syndrome: role of iron dysmetabolism. Free Radic Biol Med, in press; 2017.
[18] Di Domenico, F.; Tramutola, A.; Foppoli C.; Head, E.; Perluigi, M.; Butterfield, D.A. mTOR in Down syndrome: role in Ab and tau neuropathology and transition to Alzheimer disease-like dementia. Free Radic Biol Med, in press; 2017. 8
[19] Head E.; Helman A.; Powell,D; Schmitt, F. Down syndrome, beta-amyloid and neuroimaging. Free Radic Biol Med, in press; 2017.
[20] Hamlett, E.; Ledreux A.; Potter H.; Chial, H; Espinosa, J.; Bettcher,B.M.; Granholm, A.C. Exosomal biomarkers in Down syndrome and Alzheimer’s disease. Free Radic Biol Med, in press; 2017.
[21] Fructuoso, M.; Rachdi, L.; Philippe, E.; Denis, R.G.; Magnan, C.; Le Stunff, H.; Janel, N.; Dierssen, M. Increased levels of inflammatory plasma 1 markers and obesity risk in a mouse model of Down syndrome. Free Radic Biol Med, in press; 2017.
D. Allan Butterfield
Marzia Perluigi
Department of Chemistry and Sanders-Brown
Department of Biochemical Sciences
Center on Aging, University of Kentucky
Sapienza University of Rome
Lexington, KY 40506 USA
Rome, Italy
9
PII: DOI: Reference:
S0891-5849(17)31158-9 https://doi.org/10.1016/j.freeradbiomed.2017.10.374 FRB13491
To appear in: Free Radical Biology and Medicine Cite this article as: D. Allan Butterfield and Marzia Perluigi, Down Syndrome: From Development to Adult Life to Alzheimer Disease, Free Radical Biology and Medicine, https://doi.org/10.1016/j.freeradbiomed.2017.10.374 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 galley proof before it is published in its final citable 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.
EDITORIAL Down Syndrome: From Development to Adult Life to Alzheimer Disease
Down syndrome (DS) is most common genetic cause of intellectual disability resulting from trisomy of the distal part of chromosome 21 (Chr21). Life expectancy for the DS population has significantly improved, although with increasing age pathological dysfunctions are exacerbated and intellectual disability degenerates in most cases to a form of dementia that closely resembles that of Alzheimer disease (AD). Although genetic defects are the crucial determinants of the majority of clinical presentations of the disease such as craniofacial abnormalities, small brain size, accelerated aging, and cognitive decline, other factors play a crucial role in determining the severity of pleiotropic phenotypes. Trisomy 21 is associated with a genetic instability that affects not only Chr21 but also other disomic genes that ultimately results in a wide variability and complex set of clinical features [1, 2]. Brain development and intellectual disabilities are the most striking features of trisomy of Chr21 [3, 4], and language, learning and memory appear to be severely affected [5]. The neuropathology of DS results from the combination of several factors, both genetic and non-genetic, among which oxidative stress, altered glucose metabolism, mTOR activation, mitochondrial dysfunction, altered proteostasis network, including the endosome/lysosome system, are key players and major contributors to neuronal degeneration. The comprehension of degenerative phenomena related to accelerated aging and neurodegeneration is one of the major challenges of research in this field, both at molecular and clinical levels. In the last decades, DS neuropathology has become an attractive field of research to study the contribution of accelerated aging in order to correlate genetic defects to pathological phenotypes and also to understand the role of neurogenesis defects and brain development abnormalities that ultimately results in
1
cognitive decline. Indeed, DS individuals, typically between age of 40-50, show neuropathological hallmarks of Alzheimer disease (AD), including deposition of senile plaques containing amyloid beta-peptide (Aβ), neurofibrillary tangles composed of hyperphoshorylated tau, and cholinergic and serotonergic reduction [6, 7]. AD is virtually inevitable in DS subjects; however, the onset of dementia typically appears in DS adults over the age of 50 years of age, suggesting a quite long prodromal phase in which clinical signs are virtually undetectable (reviewed in [8]). The precise mechanisms by which trisomy 21 lead to the early-onset of AD-like neuropathology and cognitive decline remain to be elucidated. Age-dependent A accumulation provides a significant opportunity for development of targeted clinical trials in people with DS to slow or, ideally, prevent, the onset of AD. Further, progress of sophisticated methodological approaches may allow identification of clinical markers of AD in DS based on plasma and neuroimaging studies. This Special Issue of Free Radical Biology & Medicine aims to provide the scientific community an overall picture of deregulated pathways that are responsible for the main pathological features of the disease, in particular the Alzheimer-like neuropathology, by also discussing putative therapeutic strategies that may slow or attenuate clinical manifestations. The authors of this Special Issue discuss clinical signs and symptoms, pathology, neurogenesis, endosome/lysosomes/exosomes, mitochondrial changes, iron dyshomeostasis and oxidative stress, mTOR activation and downstream sequelae, therapy based on estrogen alterations and use of hormone replacement therapy in women with DS, and finally a mouse model of DS. Specifically, in the section of this Special Issue entitled Clinical, Pathological, and Neurodevelopmental Characteristics of Down Syndrome (DS) and DS with Alzheimer Disease (AD), the paper from Prof. Strydom [9] reviews current knowledge on clinical diagnosis and presentation of dementia in DS in comparison with familial AD (FAD) due to APP mutations and APP duplication. The authors suggest that the clinical presentations in 2
DS are similar to the clinical features associated with APP mutations, known to have an increased Aβ42/ Aβ40 ratio in brain, and highlight the relative lack of vascular complications associated with cerebral amyloid angiopathy in DS in comparison with those rare individuals with AD due to duplication APP. Prof. Busciglio [10] examines the role of astrocytes in dendritic spine alterations and more specifically the involvement of astrocytesecreted thrombospondin-1 (TSP-1) deficits in spine and synaptic neuropathology in DS. He posits that defects in both spine morphology and spine density may underlie alterations in neuronal and synaptic plasticity, ultimately affecting cognitive ability. Prof. Bartesaghi [11] discusses the role of some of the triplicate genes such as DYRK1A, APP, RCAN1 and OLIG1/2, which seem to be critical determinants of neurodevelopmental alterations because they affect both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Furthermore, pathways downstream to these selected genes may represent strategic targets for the design of possible therapeutic interventions. In the section of this Special Issue entitled Brain Cell Biology and Neurodegeneration in DS and DS with AD, Prof. Potier [12] reviews current literature that converge towards the hypothesis that excitatory-inhibitory neurotransmission imbalance occurs in DS, likely early during development. Prof. Potier posits that it is likely learning and memory impairments linked to intellectual disabilities in DS could result from synaptic plasticity deficits and excitatory inhibitory alterations leading to changes in neuronal circuitry in the brain of affected individuals. Prof. Nixon [13] reviews current research on endocytic/lysosomal dysfunction in DS and AD, the role of APP/βCTF in initiating this dysfunction, and the contribution of additional trisomy 21 genes in accelerating endosomal-lysosomal impairment in DS. Collectively, these studies demonstrate that both DS and AD neuropathologies show defects in endocytosis and lysosomal function, appearing at the earliest stages of disease development and progress to widespread failure of intraneuronal waste clearance, neuritic dystrophy and consequent neuronal 3
death. Prof. Mobley [14] discusses the role of intracellular signaling from endosomes in the development and maintenance of the nervous system and how the disruption of this system impacts neurodegeneration in DS. The signaling endosomes represents a well suited system for the transmission of trophic factor signals over long distances from axons and dendrites to the cell bodies of neurons. Changes in endosome structure in DS and AD are present early in these disorders; experimental evidence for disruption of signaling endosome function in other disorders of the nervous system also is reviewed. Prof. Schupf [15] reviews current studies on the role of estrogen-related factors in age at onset and risk for AD in women with DS, a population at high risk for early onset of dementia. The studies are consistent with the notion that early age of menopause and low levels of endogenous bioavailable estradiol in postmenopausal women are associated with earlier age at onset and overall risk for dementia. Accordingly, several studies have shown a protective role for estrogen against AD in DS through a number of biological actions. In the section of this SI entitled Oxidative Stress-related Neurobiology in DS and DS with AD, Prof. Vacca [16] focuses on recent studies demonstrating mitochondrial impairment in DS, focusing on alterations of the molecular pathways controling mitochondrial function. The effects and molecular mechanisms by which naturally occurring and chemically synthetized drugs might exert neuroprotective effects through modulation of mitochondrial function and attenuation of oxidative stress also are discussed. Prof. Perluigi [17] discusses recent findings demonstrating the accumulation of oxidative damage in DS and in particular the specific dysregulation of iron metabolism. Iron dysmetabolism is a well-recognized factor that contributes to neurodegeneration, but how and to what extent the concerted loss of iron dysheomestasis and increased OS occur in DS is not well understood. New insights are presented. Prof. Butterfield [18] reviews recent research highlighting the complex role of mTOR in age dependent cognitive decline in AD and AD-like dementia in DS. Aberrant mTOR signaling is associated with the 4
presence of two hallmarks of AD pathology, senile plaques and neurofibrillary tangles. Oxidative stress, associated with Chr21-related Aβ and mitochondrial alterations, may contribute to this linkage of mTOR to AD-like neuropathology in DS. In the final section of this Special Issue of FRBM entitled Potential Neuroimaging and Plasma-resident Biomarkers in DS and DS with AD and a Mouse Model Thereof, Prof. Head [19] focuses on the role of Aβ in AD pathogenesis in DS and discusses current approaches for imaging Aβ in vivo. The mechanisms through which Aβ deposits with age, its posttranslational modifications and detection in biofluids also are described. In addition, brain imaging for Aβ, including those by positron emission tomography and ligands that bind Aβ, are summarized in her paper. Prof. Granholm [20] discusses findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS suggesting a close connection between neuroinflammatory pathways, oxidative stress, neural-derived exosomes, and exosome-mediated signaling. The increased neuroinflammatory state observed in people with DS may affect plasma-resident neuronal exosomal AD biomarkers. Moreover, the discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Prof. Dierssen [21] investigates the role of metabolic/inflammatory axis in DS. By using Ts65Dn mice, a validated DS mouse model, for the study of obesity-related inflammatory markers, the authors show that increased adiposity and pro-inflammatory adipokines lead to low-grade inflammation and are important players in the propensity to obesity in DS.
Taken together, the papers in this Special Issue of Free Radical Biology & Medicine on “Down Syndrome: From Development to Adult Life to Alzheimer Disease” provide a comprehensive picture of DS throughout the lifespan. New insights into molecular processes involved in the appearance of cognitive decline, age-dependent progression to 5
AD-like neuropathology and dementia, and potential therapeutic strategies to slow or stop this progression are provided. As the Co-Editors of this Special Issue of FRBM we are pleased to assemble in one locus these important papers. We believe the readers of this Special Issue will learn more of DS and how Chr 21 triplication can provide insights into AD.
6
References [1]
Dierssen, M.; Herault, Y.; Estivill, X. Aneuploidy: from a physiological
mechanism of variance to Down syndrome. Physiol Rev 89:887-920; 2009.
[2]
Antonarakis, S. E.; Lyle, R.; Chrast, R.; Scott, H. S. Differential gene
expression studies to explore the molecular pathophysiology of Down syndrome. Brain Res Brain Res Rev 36:265-274; 2001.
[3]
Devenny, D. A.; Krinsky-McHale, S. J.; Sersen, G.; Silverman, W. P.
Sequence of cognitive decline in dementia in adults with Down's syndrome. J Intellect Disabil Res 44 ( Pt 6):654-665; 2000.
[4]
Devenny, D. A.; Wegiel, J.; Schupf, N.; Jenkins, E.; Zigman, W.; Krinsky-
McHale, S. J.; Silverman, W. P. Dementia of the Alzheimer's type and accelerated aging in Down syndrome. Sci Aging Knowledge Environ 2005:dn1; 2005.
[5] Carlesimo, G. A.; Marotta, L.; Vicari, S. Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down's syndrome. Neuropsychologia 35:71-79; 1997.
[6] Lott, I. T. Neurological phenotypes for Down syndrome across the life span. Prog Brain Res 197:101-121; 2012.
[7]
Wisniewski, H. M.; Rabe, A. Discrepancy between Alzheimer-type
neuropathology and dementia in persons with Down's syndrome. Ann N Y Acad Sci 477:247-260; 1986.
[8] Wiseman, F. K.; Al-Janabi, T.; Hardy, J.; Karmiloff-Smith, A.; Nizetic, D.; Tybulewicz, V. L.; Fisher, E. M.; Strydom, A. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16:564-574; 2015. [9] Zis, P.; Strydom A. Clinical aspects and biomarkers of Alzheimer’s disease in Down syndrome. Free Radic Biol Med, in press; 2017.
7
[10] Torres, M.D.; Garcia, O.; Tang C’ Busciglio, J. Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med, in press; 2017.
[11] Stagni, F.; Giacomini, A.; Emili M.; Guidi, S.; Bartesaghi, R. Neurogenesis impairment: an early developmental defect in Down syndrome. Free Radic Biol Med, in press; 2017.
[12] de San Martinm J.Z.; Delabar, J.-M.; Bacci, A.; Potier, M.-C. GABAergic overinhibition, an exciting hypothesis for cognitive deficits in Down syndrome. Free Radic Biol Med, in press; 2017.
[13] Colacurcio, D.J.; Pensalfini, A.; Yiang, Y.; Nixon, R.A. Dysfunction of Autophagy and Endosomal-lysosomal Pathways: Roles in Pathogenesis of Down Syndrome and Alzheimer’s Disease. Free Radic Biol Med, in press; 2017.
[14] Chen, X.-Q.; Sawa, M.; Mobley, W.C. Dysfunction of autophagy and endosomal-lysosomal pathways: roles in pathogenesis of Down syndrome and Alzheimer’s disease. Free Radic Biol Med, in press; 2017.
[15] Schupf, N.; Lee, J.H.; Pang, D.; Zigman, W.B.; Tycko, B.; Sharon KrinskyMcHale, S.; Silverman, W. Epidemiology of Estrogen and Dementia in Women with Down Syndrome. Free Radic Biol Med, in press; 2017.
[16] Valenti, D.; Braidy, N.; De Rasmo, D.; Signorile, A.; Rossi, L.; Atanasov, A.G.; Volpicella, M.; Caude, A.H.; Nabavi, S.M.; Vacca, R.A. Mitochondria as pharmacological targets in Down syndrome. Free Radic Biol Med, in press; 2017.
[17] Barone E.; Arena A.; Head, E.; Butterfield D.A; Perluigi, M. Disturbance of redox homeostasis in Down Syndrome: role of iron dysmetabolism. Free Radic Biol Med, in press; 2017.
[18] Di Domenico, F.; Tramutola, A.; Foppoli C.; Head, E.; Perluigi, M.; Butterfield, D.A. mTOR in Down syndrome: role in Ab and tau neuropathology and transition to Alzheimer disease-like dementia. Free Radic Biol Med, in press; 2017. 8
[19] Head E.; Helman A.; Powell,D; Schmitt, F. Down syndrome, beta-amyloid and neuroimaging. Free Radic Biol Med, in press; 2017.
[20] Hamlett, E.; Ledreux A.; Potter H.; Chial, H; Espinosa, J.; Bettcher,B.M.; Granholm, A.C. Exosomal biomarkers in Down syndrome and Alzheimer’s disease. Free Radic Biol Med, in press; 2017.
[21] Fructuoso, M.; Rachdi, L.; Philippe, E.; Denis, R.G.; Magnan, C.; Le Stunff, H.; Janel, N.; Dierssen, M. Increased levels of inflammatory plasma 1 markers and obesity risk in a mouse model of Down syndrome. Free Radic Biol Med, in press; 2017.
D. Allan Butterfield
Marzia Perluigi
Department of Chemistry and Sanders-Brown
Department of Biochemical Sciences
Center on Aging, University of Kentucky
Sapienza University of Rome
Lexington, KY 40506 USA
Rome, Italy
9