Apelin, a promising target for Alzheimer disease prevention and treatment

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Apelin, a promising target for Alzheimer disease prevention and treatment Javad Masoumia,b, Morteza Abbaslouic, Reza Parvand, Daryoush Mohammadnejade, ⁎ Graciela Pavon-Djavidf, Abolfazl Barzegarig, Jalal Abdolalizadehe,c, a

Rafsanjan University of Medical Sciences, Rafsanjan, Iran Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran d Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran e Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Unirversite Paris 13, Villetaneuse, France g Research Centre for Pharmaceotical Nanotechnology, Tabriz University (Medical Sciences), Tabriz, Iran b c

A R T I C LE I N FO

A B S T R A C T

Keywords: Alzheimer disease Apelin Amyloid beta Central nervous system Oxidative stress

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high outbreak rates. It is estimated that about 35 million individuals around the world suffered from dementia in 2010. AD is expected to increase twofold every 20 years and, by 2030, approximately 65 million people could suffer from this illness. AD is determined clinically by a cognitive impairment and pathologically by the production of amyloid beta (Aβ), neurofibrillary tangles, toxic free radicals and inflammatory mediators in the brain. There is still no treatment to cure or even alter the progressive course of this disease; however, many new therapies are being investigated and are at various stages of clinical trials. Neuropeptides are signaling molecules used by neurons to communicate with each other. One of the important neuropeptides is apelin, which can be isolated from bovine stomach. Apelin and its receptor APJ have been shown to broadly disseminate in the neurons and oligodendrocytes of the central nervous system. Apelin-13 is known to be the predominant neuropeptide in neuroprotection. It is involved in the processes of memory and learning as well as the prevention of neuronal damage. Studies have shown that apelin can directly or indirectly prevent the production of Aβ and reduce its amounts by increasing its degradation. Phosphorylation and accumulation of tau protein may also be inhibited by apelin. Apelin is considered as an anti-inflammatory agent by preventing the production of inflammatory mediators such as interleukin-1β and tumor necrosis factor alpha. It has been shown that in vivo and in vitro anti-apoptotic effects of apelin have prevented the death of neurons. In this review, we describe the various functions of apelin associated with AD and present an integrated overview of recent findings that, in general, recommend apelin as a promising therapeutic agent in the treatment of this ailment.

1. Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and it is considered the most prevalent form of dementia in the

elderly. Pathologically, it is characterized by intracellular neurofibrillary tangles (NFTs) and extracellular amyloid beta (Aβ) protein deposits that contribute to senile plaques (Selkoe, 1991). The mutation in the amyloid precursor protein (APP), presenilin (PS) 1 and 2 genes

Abbreviations: AAA, Abdominal aortic aneurysm; ABCA1, ATP-binding cassette transporter A1; ACE, Angiotensin converting enzyme; ACh, Acetylcholine; AChE, Acetyl choline esterase; AD, Alzheimer's disease; ApoE, Apo lipoprotein E; AMPK, AMP-activated protein kinase; APP, Amyloid precursor protein; AT1R, Angiotensin II type 1 receptors; AVP, arginine vasopressin; Aβ, Amyloid beta; BACE1, β-site APP-cleaving enzyme 1/β-secretase; BBB, blood-brain barrier; CAT, Catalase; cGMP, Guanosine monophosphate; CNS, Central nervous system; eNO, Endothelial nitric oxide; eNOS, Endothelial nitric oxide synthase; ERK, Extracellular signal-regulated kinase; FDA, Food and Drug Administration; GLP-1, Glucagon-like peptide-1; GSH-Px, Glutathione peroxidase; GSK, Glycogen synthase kinase; H2O2, Hydrogen peroxide; I/R, Ischemia/reperfusion; ICAM-I, Intercellular adhesion molecule I; IFN, Interferon; IL, Interleukin; ICV, intracerebroventricular; IP3, Inositol triphosphate; JNK, c-Jun N-terminal kinase; LRP-1, Low-density lipoprotein receptor related protein-1; MAPK, Mitogen-activated protein kinase; MEK, Mitogen activated protein kinase kinase; MCP-1, Monocyte chemoattractant protein-1; MIP-1α, Macrophage inflammatory protein-1α; MPO, Myeloperoxidase; NEP, Neprilysin; NFT, Neurofibrillary tangles; NMDAR, N-methyl D-aspartate receptor; OxS, Oxidative stress; PI3K, phosphatidylinositide 3-kinases; PKB/AKT, Protein kinase B; PKC, Protein kinase C; PLA2, Phospholipase A2; PS, Presenilin; PTZ, Pentylenetetrazole; QUIN, Quinolinic acid; RAGE, Receptor for advanced glycation end products; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; SD, Serum deprivation; SOD, Superoxide dismutase; TGF, Transforming growth factor; TNF-α, Tumor necrosis factor alpha ⁎ Corresponding author at: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail address: [email protected] (J. Abdolalizadeh). https://doi.org/10.1016/j.npep.2018.05.008 Received 7 March 2018; Received in revised form 19 May 2018; Accepted 20 May 2018 0143-4179/ © 2018 Elsevier Ltd. All rights reserved.

Please cite this article as: Masoumi, J., Neuropeptides (2018), https://doi.org/10.1016/j.npep.2018.05.008

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significant role in neuroprotection (Cheng et al., 2012; Zhen et al., 2013). In humans, apelin mRNA are expressed in various parts of the central nervous system such as the hippocampus, thalamus, hypothalamus, the basal forebrain, frontal cortex, corpus callosum, amygdala, substantia nigra, pituitary, and the spinal cord, as well as in peripheral organs such as placenta, kidney, heart, lung, and mammary gland (Kleinz and Davenport, 2005). Early on, apelin was recognized as an effective factor in lowering blood pressure by increasing endothelial nitric oxide (eNO) (Tatemoto et al., 2001b). APJ receptor identified as a coreceptor for human immunodeficiency virus type 1. It has been demonstrated that apelin by binding to APJ can block virus entry into the cells expressing APJ (Cayabyab et al., 2000). Experimental studies indicated that apelin led to protection against heart I/R injury in rats (Zeng et al., 2009), reducing in left ventricular preload and afterload and improving of cardiac contractility in C57/Bl/6 mice (Ashley et al., 2005), and reducing of the infarct size and normalization of the impaired cardiac function in C57BL/6 J mice with myocardial infarction (Xu et al., 2017). In patients along with chronic heart failure, apelin treatment caused peripheral and coronary vasodilatation and augmented cardiac output (Japp et al., 2010). Also it has been shown that apelin-13 plays an important role in improvment of post myocardial infarction repair through myocardial progenitor cells elevation in the infarcted hearts (Li et al., 2012). It has been shown that apelin-13 administration in patients with type 2 diabetes improves insulin sensitivity (Gourdy et al., 2017). Intravenous injection of apelin in mice potentially lowered blood glucose through elevating of glucose utilization in skeletal muscle and adipose tissue, and on the other hand, in high fat diet C57Bl6/J mice with hyperinsulinemia, hyperglycemia and obesity, apelin injection restored glucose tolerance and increased glucose utilization in peripheral tissues (Dray et al., 2008). In obes mice, apelin injection decreased body weight, adiposity, and blood triglycerides and fatty acids (Castan-Laurell et al., 2011). In rats with renal I/ R injury, Apelin-13 treatment blocked increasing of inflammatory mediators and transforming growth factor (TGF)-β1, as well as apoptosis and subsequently, normalized the injury induced renal dysfunction (Chen et al., 2015b). Apelin plays a key role in inducing angiogenesis in phatological conditions including myocardial infarction, ischemic stroke, critical limb ischemia, tumor, cirrhosis, obesity, diabetes and other related diseases (Wu et al., 2017). Apelin expression increased in variety of cancers and indicated that plays a role in the progression of various cancers including lung cancer, gastroesophageal cancer, colonic cancer, hepatocellular carcinoma, prostate cancer, endometrial cancer, oral squamous cell carcinoma and brain cancer (Yang et al., 2016a). Different functions of apelin in the CNS have been documented in various studies. ICV administration of apelin-13 in rats caused significantly increasing in drinking behavior and water intake and also elevated plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone and decreased plasma levels of prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Taheri et al., 2002). It has been revealed that apelin has a diuretic activity and play an crucial role in body fluid homeostasis control by regulation of arginine vasopressin (AVP) neurons activity and AVP release (De Mota et al., 2004). ICV administration of apelin in lactating rats inhibited the activity of magnocellular and parvocellular oxytocin neurons and subsequently, reduced the amount of milk ejected (Bodineau et al., 2011). It has been reported that apelin-13 with dopamine, NO and prostaglandins cooperation, involved in the regulation of behavioral, endocrine and homeostatic responses in the CNS (Jaszberenyi et al., 2004).

causes high levels of Aβ production, thus resulting in the early onset of AD. Moreover, the ε4allele of Apo lipoprotein E (ApoE) is associated with an increased risk of late-onset AD (St George-Hyslop, 2000; Takeda et al., 2004). Other important factors involved in the pathogenesis of AD include neurotransmitter dysfunctions such as acetylcholine (Coyle et al., 1983), N-methyl D-aspartate receptor (NMDAR)mediated excitotoxicity (Hynd et al., 2004), oxidative damage (Lin and Beal, 2006), and inflammation from cytokines and chemokines (Akiyama et al., 2000). Apelin is a neuropeptide isolated from bovine stomach extracts and is used by neurons to communicate with each other. It is an endogenous ligand for the APJ receptor (Tatemoto et al., 1998). The apelin/APJ system has several important functions in the body, such as blood pressure regulation, cardiac contractility, immunity, glucose metabolism, water homeostasis, cell proliferation, angiogenesis, and neuroprotection (Wu et al., 2017). A study has been shown that serum levels of apelin-13 decreased in AD patients (EREN et al., 2012). In rats with cerebral ischemia/reperfusion (I/R) injury, treatment by apelin-13 significantly decreased neurological deficits and the infarct volume (Xin et al., 2015). In cerebral ischemia mice model, apelin-13 injection significantly protected blood-brain barrier (BBB) from injury through decreasing BBB permeability, elevated vascular endothelial growth factor, upregulated endothelial nitric oxide synthase (eNOS), and downregulated inducible NOS (Chu et al., 2017a). In SOD1G93A mouse model of amyotrophic lateral sclerosis, it has been indicated that apelin deficiency caused decreasing the number of motor neurons and earlier appearance of disease phenotypes and also, accelerated the progression of disease via microglia activation in spinal cord (Kasai et al., 2011). In mice with glioblastoma, an aggressive brain tumor, APJ antagonist, MM54,treatment caused significantly decrease in tumor growth and disrupted the expansion of tumor associated neurological symptoms (Harford-Wright et al., 2017). It is reported that intracerebroventricular (ICV) injection of apelin-13 in traumatic brain injury mice model resulted in reducing of brain damage via autophagy suppressing (Bao et al., 2015). In stressed rats it has been shown that apelin-13 injection accelerated antidepressant-like and recognition memory improving activities via activating phosphatidyl inositol 3-kinases (PI3K) and extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathways. It has been revealed that the hippocampus is a Critical Site of apelin antidepressant-like activity (Li et al., 2016; Xiao et al., 2018). In Parkinsonism rats, apelin-13 injection into the substantia nigra significantly reduced cognitive impairments (Haghparast et al., 2018). In this review, we examine the various factors and mechanisms mediated by apelin that may contribute to the prevention and treatment of AD. 2. Apelin The APJ receptor ligand apelin firstly in 1998 was segregated from bovine stomach tissue. Human preproapelin gene located on chromosome Xq25–26.1. The apelin preproproteins consist of 77 amino acid residues that are cleaved into biologically active C-terminal fragments of various sizes. The apelin peptides, including 13 (65–77), 17 (61–77), and 36 (42–77) amino acids (Fig. 1), are all capable of binding to APJ (Lee et al., 2000a; Tatemoto et al., 1998). Among apelin isoforms, apelin-13 has the highest plasma concentration and plays the most

3. The pathogenesis of AD and the targets of apelin 3.1. Apelin/endothelial nitric oxide and AD Fig. 1. Amino acid sequences of various biologically active forms of apelin. a) apelin13 (65–77), b) apelin17 (61–77), c) apelin36 (42–77).

The absence of eNO in the brain increases the amount of APP and β2

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catabolism (Iwata et al., 2000). The elimination of NEP in mice causes a defect in injected exogenous Aβ and endogenous Aβ catabolism, and leads to the deposition of Aβ in the brain (Iwata et al., 2001). A study showed that by transfer of the NEP gene to transgenic mouse models of amyloidosis, the Aβ deposition reduced along with improvement in neurodegenerative alterations in the frontal cortex and hippocampus (Marr et al., 2003). It has been revealed that apelin-13, by up-regulating the ABCA1 in THP-1 macrophage-derived foam cells, elevates cholesterol efflux and decreases cholesterol levels in the cells. Apelin does this by activating protein kinase Cα(PKCα) and phosphorylation of ABCA1, preventing its cleavage by calpain (Liu et al., 2013). A study has shown that apelin-13, by inhibiting the activity of calpain, increased the level of ABCA1 protein in the pheochromocytoma cell line (PC-12 cells with neuroendocrine cell characteristics) and reduced intracellular lipid accumulation by stimulation of cholesterol efflux. Apelin also decreased the levels of Aβ in these cells by decreasing BACE1 activity and increasing NEP activity a(Xinping et al., 2014). In APP/PS1 mice, apelin-13 injection improves memory and cognition. Furthermore, apelin increases the degradation and clearance of Aβ in the hippocampus and prefrontal lobe; it also reduces the amount of Aβ by decreasing BACE1 activity and increasing activity of NEP. In these mice, apelin also increased the level of ABCA1 protein in the hippocampus and prefrontal cortex (Xinping, 2014).

site APP-cleaving enzyme 1(BACE1) expression, which leads to an increase in the production of Aβ. In the presence of eNOS and NO production, these processes are inhibited and the amount of Aβ decreases (Austin et al., 2013; Austin et al., 2010). eNO is effective in Aβ clearance, as it is responsible for increasing the elasticity of cerebral blood vessels, preventing their stiffening along with modulating the endothelial Aβ transport proteins, including low-density lipoprotein receptor related protein-1 (LRP-1), which mediates the efflux of Aβ from the brain. In addition, the receptor for advanced glycation end products (RAGE) mediates the influx of Aβ into the brain (Katusic and Austin, 2013). Furthermore, eNO increases synaptic plasticity by the activation of soluble guanylyl cyclase and the increased production of cyclic guanosine monophosphate (cGMP). On the other hand, NO/cGMP signaling is an essential mechanism required for memory formation (Bon and Garthwaite, 2003; Hopper and Garthwaite, 2006). The eNO can also increase acetylcholine (ACh) secretion, an essential neurotransmitter for learning and memory, from the basal forebrain, nucleus accumbens, and dorsal striatum as mediated by cGMP (Prast and Philippu, 2001). It has been indicated that apelin via activating L-arginine/NOS pathway and eNOS phosphorylation is a potential activator of eNOS in vasculatures and consequently, production of eNO. (Tatemoto et al., 2001a; Zhong et al., 2007). In neonatal rats, apelin treatment caused significantly elevation in lung cGMP that this effect of apelin mediated by NOS activation (Visser et al., 2010). Apelin may indirectly decrease the amount of Aβ and improve memory in AD by increasing the production of eNO from the cerebral vascular endothelium (Fig. 2).

3.3. Excitotoxicity and AD Excitotoxicity is one of the most recognized processes of neuronal death that plays a role in the pathogenesis of many CNS diseases, especially AD. The process of excitotoxicity is triggered by the excess secretion of synaptic glutamate, which in turn activates the postsynaptic glutamate receptor. The majority of these receptors are subtypes of NMDARs, which has a high permeability for calcium ions (Ca2+) and mediate post-synaptic Ca2+ influx (Albin and Greenamyre, 1992; Sattler and Tymianski, 2001). An excessive intracellular Ca2+, by increasing the activity of NOS and phospholipase A2 (PLA2), leads to the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) such as peroxynitrite (OONO−), and to the activation of proteases such as calpain, which ultimately leads to cell death (Ciani et al., 1996; Wang and Qin, 2010). The active form of calpain, a calcium-dependent cysteine protease, is revealed in 50% to 70% of tau

3.2. Apelin, ATP-binding cassette transporter A1, neprilysin, and Aβ The presence of a proportional amount of cholesterol is essential for the normal function of neural cells, but its surplus causes cleavage of the APP and the production and accumulation of Aβ. It has been shown that ATP-binding cassette transporter A1 (ABCA1) with ApoE lipidation results in the efflux of cholesterol from the neurons, thereby reducing the production and accumulation of Aβ in the CNS (Kim et al., 2007; Wahrle et al., 2008). Researchers have found that removing the ABCAI increased the amount of Aβ in the brain of mouse models with AD. This was attributed to the decrease in apoE lipidation and elevated cholesterol level in the neurons (Koldamova et al., 2005; Wahrle et al., 2005). Neprilysin (NEP) is a Aβ- degrading enzyme that plays a key role in Aβ

Fig. 2. Apelin stimulate eNO releasing that play role in inhibition of Aβ production, synaptic plasticity and Aβ clearance in brain. eNO: endothelial nitric oxide, Aβ: amyloid beta, APP: amyloid precursor protein, BACE1: β-site APP-cleaving enzyme 1/ β-secretase 3

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3.4. Oxidative damage and AD

neurofibrillary pathology in AD. The calpain causes a breakdown of P35 to produce P25, which is associated with tau hyperphosphorylation caused by disrupting the cytoskeleton and resulting in the death of a neuron (Adamec et al., 2002; Lee et al., 2000b). Another factor in neurotoxicity is quinolinic acid (QUIN), which stimulates IL-1β production acting as an important mediator of AD pathogenesis in human astrocytes; it is an important agent for astroglial activation, dysregulation, and cell death too (Ting et al., 2009). The QUIN-induced cytotoxic effects on neurons is mediated by the formation of ROS and free radicals attributed to the high activity of NMDARs (Braidy et al., 2009; Santamaría et al., 2001). In addition, QUIN can induce tau phosphorylation by activating the NMDARs (Rahman et al., 2009). Apelin activates cellular survival signals through inositol triphosphate (IP3), PKC, mitogen-activated protein kinase 1/2 (MEK1/2), Raf/ERK1/2, and AKT/protein kinase B (PKB) in neurons protecting them against NMDAR-dependent excitotoxicity. Furthermore, apelin inhibits excitotoxic signaling by decreasing the activity of NMDAR and calpain, and adjusting the NMDAR subunit NR2B phosphorylation at serine 1480 (Cook et al., 2011; O'Donnell et al., 2007). Apelin-13 can also reduce intracellular accumulation of NMDAR-induced Ca2+, which is an important factor in excitotoxicity (Zeng et al., 2010).On the other hand, apelin protects the hippocampal neurons against QUIN-induced excitotoxicity (O'Donnell et al., 2007). These functions indicate that apelin is a potent inhibitor of excitotoxicity, specifically when induced by NMDAR (Fig. 3). Solid line indicate the blocking and the dashed line indicate the inhibition or decrease of activity. PKC: protein kinase C, NMDAR: Nmethyl D-aspartate receptor, ERK: extracellular signal-regulated kinase, IP3: inositol triphosphate, MEK: mitogen activated protein kinase kinase, NOS: nitric oxide synthase, RNS: reactive nitrogen species, ROS: reactive oxygen species, QUIN: quinolinic acid

3.4.1. Oxidative stress Oxidative stress (OxS) is characterized by an imbalance between the pro-oxidants and antioxidants in the body (Sies, 1991). The pro-oxidants produce ROS such as superoxide anion (O2−) and hydrogen peroxide (H2O2) during normal metabolism, and these perform several important functions in the body. The excessive production of O2– and H2O2 can lead to tissue and molecular damage, such as damage to proteins, lipids, amino acids, and nucleic acids (Fang et al., 2002; Halliwell, 1992). OxS is involved in the pathophysiology of many neurodegenerative diseases, especially AD, occurring earlier than plaque pathology in the brain (Gilgun-Sherki et al., 2001; Nunomura et al., 2001). In AD patients, mitochondrial dysfunction is one of the main causes of the production of ROS and free radicals in the brain. The reduction of activity in the mitochondrial enzyme complexes, including cytochrome oxidase, pyruvate dehydrogenase complex, and α-ketoglutarate dehydrogenase complex, has been observed in AD. The changes in these key enzymes lead to abnormal ROS production (Zhu et al., 2004). The OxS, through activation of glycogen synthase kinase-3 (GSK-3) and c-Jun N-terminal kinase (JNK)/p38MAPK, causes tau phosphorylation and increases the expression of BACE1, respectively, thus increasing the production of NFTs and Aβ, which are considered the most important factors in AD pathogenesis (Lovell et al., 2004; Sahara et al., 2008; Tamagno et al., 2005). Several studies have shown that apelin improves the mitochondrial function and decreases the ROS production in different tissues. In skeletal muscle, apelin enhances the activity of mitochondrial enzymes and mitochondrial biogenesis markers such as citrate synthase, cytochrome c oxidase, and β-hydroxyacyl-CoA dehydrogenase. Secondly, apelin increases both, the protein content of mitochondrial respiratory chain proteins as well as the proteins involved in the assembly of mitochondrial respiratory chain complexes including chaperone proteins such as HSP70, HSP60, and mtHSP70 (Frier et al., 2009). In the muscle, it was observed that apelin increases the oxidative phosphorylation capacity and the protein expression of complex II, III, and V (Attané et al., 2012). In adipocytes, apelin prevents the production and release of ROS by stimulating the expression of antioxidant enzymes through mitogenactivated protein kinase (MAPK)/ERK and AMP-activated protein kinase (AMPK) pathways and inhibiting the expression of pro-oxidant enzymes via the AMPK pathway (Than et al., 2014). In the heart organ, apelin prevents ROS-dependent hypertrophy by increasing antioxidant activity; moreover, apelin's structural analogues inhibit production of mitochondrial ROS and reduce apoptosis (Foussal et al., 2010; Pisarenko et al., 2015). In cortical neurons, dose-dependent apelin can reduce ROS production (Zeng et al., 2010). eNO also plays a role in mitochondrial biogenesis by activation of soluble guanylyl cyclase and the formation of cGMP (Nisoli et al., 2004); the expression of eNOS and the production of eNO is provoked by apelin (Tatemoto et al., 2001a). 3.4.2. Antioxidants Antioxidants are the key molecules inhibiting cellular damage mediated by ROS. It is found that in AD patients, the activity of natural antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) reduces significantly in various areas of the brain, and on the other hand, increasing the prooxidants levels leads to neurodegeneration (Casado et al., 2008; Marcus et al., 1998; Rinaldi et al., 2003). The high expression of CAT in different parts of the brain was significantly associated with decreasing the levels of APP, BACE1, Aβ, Aβ deposition, and oxidative DNA damage, and elevating the amount of Aβ degrading enzymes (Mao et al., 2012). Using an AD mouse model, researchers found that the SOD/CAT mimetic, EUK-207, protects against increased levels of oxidized nucleic acid and lipid peroxidation in the brain. Moreover, it reduces the amount of Aβ, tau, and hyperphosphorylated tau accumulation in the amygdala and hippocampus of these mice (Clausen et al., 2012). The

Fig. 3. Reduced excitotoxicity with apelin activity. The apelin reduces the activation of NMDAR and calpain, and on the other hand, by activating cellular survival signals such as Raf, ERK1/2, AKT, IP3, PKC and MEK1/2, increases cell survival. 4

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CAT also degrades H2O2 produced by the activity of Aβ in the brain (Milton, 2001). It has been shown that in mice with SOD deficiency and a high expression of APP, Aβ oligomerization and memory impairment are exacerbated, and that this phenomenon is essentially mediated by oxidative damage. The removal of SOD further causes tau phosphorylation in this mice (Murakami et al., 2011). In the AD mouse model, the overexpression of SOD reduces hippocampal superoxide, amyloid plaques, and oxidative stress, and returns lost memory to the initial level (Dumont et al., 2009; Massaad et al., 2009). It was observed that cultured mouse cortical neurons along with an adenovirus vector encoding GSH-Px, when exposed to toxic concentrations of Aβ, developed a high resistance to toxicity (Barkats et al., 2000). Moreover, the high expression of GSH-Px protects neurons against oxidative damage and cytotoxicity induced by Aβ (Ran et al., 2006). In heart and renal I/R injury, apelin is shown to increase the amount and activity of CAT, SOD, and GSH-Px enzymes, apart from reducing the formation of hydroxyl radicals and malondialdehyde, which is the final product of lipid peroxidation (Bircan et al., 2016; Pisarenko et al., 2014; Zeng et al., 2009). Furthermore, in adipocytes, apelin can increase the CAT, SOD, and GSH-Px antioxidants (Than et al., 2014). Apelin would probably be able to reduce the oxidative damage and production of Aβ and tau by increasing the amount of aforementioned antioxidants in alzheimeric brain and, on the other hand, improve memory.

caspase-3, thus reducing apoptosis (Zou et al., 2016). In the human neuroblastoma cells of the Parkinson's disease model, apelin-13 prevents against declines of cell viability and mitochondrial membrane potential, and 6-hydroxydopamine-induced increases the levels of intracellular ROS, cytochrome c, and cleaved-caspase-3 apart from reducing apoptosis (Pooresmaeili-Babaki et al., 2017). In cultured mouse cortical neurons, apelin-13 prevents the release of cytochrome c in a serum-free medium, significantly reduces the activation of caspase-3, and inhibits serum deprivation (SD)-induced neuronal death (Zeng et al., 2010). In mouse osteoblastic cells, apelin reduced the release of cytochrome c and activation of caspases- 3, 8, and 9 and prevented glucocorticoid dexamethasone, TNF-α, and SD-induced apoptosis. Apelin performed this action through the c-Jun N-terminal kinase (JNK) and PI3-K/Akt signaling pathways (Tang et al., 2007). Furthermore, in human osteoblastic cells, apelin, by increasing the expression of Bcl-2 and reducing the expression of Bax, reduced the release of cytochrome c and activation of caspase-3, thus preventing apoptosis (Xie et al., 2007). In brain-ischemic mice, intracerebroventricular injection of apelin-13 up-regulated Bcl-2, down-regulated Bax and cleaved-caspase-3, and protected neurons against apoptosis. This apelin activity was performed through activation of PI3K/Akt and ERK1/2 signaling pathways and upregulation of the AMPKα phosphorylation level (Yang et al., 2016b; Yang et al., 2014).

3.5. Apoptosis and AD

3.6. Inflammation and AD

Apoptosis is an important mechanism that leads to the death of neuronal cells in AD (Su et al., 1994). In AD patients, the brain shows an increased expression of procaspase-3 and activated caspase-3, which is a central effector enzyme in the apoptotic cascade (Louneva et al., 2008; Stadelmann et al., 1999). By proteolytic cleaving of APP Cterminal, the activated caspases produce a cytotoxic peptide (C31) that can cause apoptosis (Lu et al., 2000). Caspase-3 can directly and specifically regulate tau phosphorylation through the GSK3β kinase pathway and breaking PKB (Chu et al., 2017b). Caspase-3 proteolytically cleaves tau protein to produce a fragment called Δtau, which results in the death of neurons in AD (Chung et al., 2001). In the AD mouse model, caspase-3 activates calcineurin and initiates dephosphorylation; it is also responsible for the removal of the GluR1 subunit of the AMPA-type receptor from the postsynaptic sites, which leads to variations of glutamatergic synaptic transmission and plasticity, and is associated with hippocampal dendritic spine degeneration and decrease in hippocampal-dependent memory (D'amelio et al., 2011). In cultured neuronal cells, it has been observed that in the presence of Aβ, the expression of Bax (pro-apoptotic protein) has an incremental regulation whereas the expression of the Bcl-2 (anti-apoptotic protein) has a decreasing regulation. Moreover, the activity of caspas-3 has also increased in the presence of Aβ (Clementi et al., 2006; Paradis et al., 1996). In the hippocampus, Aβ increases Bim (Bcl-2 interacting mediator of cell death) levels and decreases Bcl-2, which leads to activating Bax, and thus to apoptotic cell death. By blocking the Bax, Aβ-induced death can be prevented (Kudo et al., 2012). In the AD mouse model, the high expression of Bcl-2 restricted the activation of caspase-9 and reduced the caspase-induced tau cleavage. Furthermore, high expression of Bcl-2 reduced the processing of APP and tau, decreased the amount of NFTs and extracellular deposits of Aβ, and improved place memory (Rohn et al., 2008). Several anti-apoptotic effects of apelin have been observed in various investigations. In rat cortical glial neurons exposed to pentylenetetrazole (PTZ), apelin-13 decreased the markers of cellular damage including ROS, intracellular calcium, cyclooxygenase-2, and caspase 3, and protected against PTZ-induced toxicity (Esmaeili-Mahani et al., 2017). In investigating the effect of apelin-13 on corticosterone-induced neuronal death in PC12 cells, it has been observed that apelin, by activating the PI3K/Akt and ERK signaling pathways, increased cell viability and decreased corticosterone-induced up-regulation of cleaved-

Several studies have shown that the levels of inflammatory cytokines and chemokines, including myeloperoxidase (MPO) (Schreitmüller et al., 2013), IL-6 and IL-1β (Blum-Degena et al., 1995), TNF-α (Fillit et al., 1991), intercellular adhesion molecule I (ICAM-I) (Frohman et al., 1991), monocyte chemoattractant protein-1 (MCP-1) (Galimberti et al., 2006), and macrophage inflammatory protein-1α (MIP-1α), increased in AD, indicating involvement of inflammation in neurodegeneration and AD pathogenesis. It has been revealed that the activity of microglia and astrocytes in AD increases and plays an important role in inflammation, plaque formation, and neurodegeneration via secretion of cytokines and chemokines (Akiyama et al., 2000). The astrocytes generate Aβ by increasing the release of IL-1β, IL-6, TNF-α, interferon-γ (IFN-γ), and TGF-β cytokines. These cytokines produced by β-secretase are responsible for the processing of APP, thus producing Aβ (Blasko et al., 2000). In human umbilical vein endothelial cells (HUVEC) and glioma cells, IL-1β by activating PKC, enhances the expression of the APP gene and its processing, leading to the production of Aβ (Buxbaum et al., 1992; Goldgaber et al., 1989). IL-1β increases the excitotoxic damage of neurons and the activation of microglial cells; meanwhile, the IL-1 receptor antagonist decreases the death of neuronal cells and the number of microglial cells after excitotoxic damage (Hailer et al., 2005). In hippocampal neurons, IL-6 causes an unusual increase in hyperphosphorylated tau proteins; furthermore, the IL-6/IL6 receptor complex increases transcription and expression of the APP (Quintanilla et al., 2004; Ringheim et al., 1998). A study on the AD mouse model showed that anti-TNF-α injections reduced the number of amyloid plaques and tau phosphorylation as well as reduced AD symptoms (Shi et al., 2011). MPO is a myeloid lineage-specific enzyme that produces hypochlorous acid from H2O2 in the presence of chloride ions, which, along with ROS, can cause oxidative damage and neurodegeneration. An association between MPO and amyloid plaques has been observed in the brain hippocampus, thus indicating its role in the pathology of AD (Ray and Katyal, 2016; Reynolds et al., 1999). The Aβ stimulates the production of MCP-1 and MIP-1 from monocytes and microglia, which can cause neuroinflammation and neurodegeneration (Meda et al., 1999; Yang et al., 2011). ICAM-1 stimulates the production of inflammatory cytokines such as IL-1α, IL-1β, IL-6, and TNF-α from astrocytes that finally leads to neurodegeneration (Lee et al., 2000c). In rats with heart failure, apelin-13 effectively inhibits vascular 5

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decrease during disease progression and a reverse correlation between angiotensin 1–7 levels and tau hyperphosphorylation in the brain cortex and hippocampus is observed (Jiang et al., 2016). Intracerebroventricular injection of angiotensin 1–7 in the AD mouse model has been shown to improve memory and cognitive impairment (Uekawa et al., 2016). It has been shown that APJ and AT1R often have a physical interaction. Apelin forms the APJ- AT1R heterodimer, placing the AT1R in a low-affinity state, and reduces the angiotensin II binding and signaling (Siddiquee et al., 2013). In ApoE-knockout mice, exogenous angiotensin II caused atherosclerosis and AAA formation; however, injecting apelin eliminated the effects of angiotensin II. The apelin and angiotensin II receptors physically interact, and it is probable that the apelin signaling inhibits the actions of angiotensin II in vascular disease by increasing eNO production and blocking angiotensin II signaling (Chun et al., 2008). Apelin-deficient and ApoE-knockout mice have displayed developed myocardial hypertrophy and dysfunction with reduced ACE2 levels. Administration of apelin-13 injections have led to increased levels of ACE2, decreased production of anion superoxide, reduced expression of genes associated with hypertrophy and fibrosis, attenuated cardiac dysfunction, fibrosis, and hypertrophy induced by angiotensin II (Zhang et al., 2017). In a similar study, it has been observed that the ACE2 decreased in apelin-deficient mice and the apelin, by activation of its receptor, APJ, enhanced the activity of the ACE2 promoter and upregulated its expression in heart failure (Sato et al., 2013) (Fig. 4). ACE: Angiotensin converting enzyme, Aβ: amyloid beta, APP: amyloid precursor protein, BACE1: β-site APP-cleaving enzyme 1/βsecretase, GSK: glycogen synthase kinase

lesions and represses the expression of inflammatory factors such as IL1β and TNF-α (Koguchi et al., 2012). In an abdominal aortic aneurysm (AAA) mouse model, apelin treatment reduced the formation of AAA and macrophage infiltration; it also decreased the expression of aortic macrophage colony-stimulating factor and mRNA levels of MCP-1, IL-6, MIP-1, and TNF-α (Leeper et al., 2009). In a focal ischemic stroke model of mice, the intranasal apelin-13 administration reduced the mRNA level of inflammatory cytokines and chemokines containing IL-1β, TNFα, and MCP-1 in the brain, and significantly reduced the activation and recruitment of microglia (Chen et al., 2015a). In rats with cerebral I/R injury, apelin-13 inhibits the activity of MPO and decreases the expression of inflammatory factors such as IL-1β, TNF-α, and ICAM-1. Moreover, apelin-13 reduces the ionized calcium-binding adapter molecule-1 (Iba1), glial fibrillary acidic protein (GFAP), and high mobility group box 1 (HMGB1) expression in these rats, indicating the inhibition of microglia, astrocytes, and other inflammatory cells (Xin et al., 2015). However, one study reports that apelin in microglial BV2 cells increases the expression of inflammatory factors including IL-1β, TNF-α, MCP-1, and MIP-1α via PI3K/Akt and ERK signaling pathways (Chen et al., 2015c). Therefore, further exploration of the role of apelin in neuroinflammation is needed. 3.7. Renin-angiotensin system and AD Evidence indicates the involvement of renin-angiotensin system in the pathogenesis of AD. The angiotensin-converting enzyme (ACE) activity increased in AD and is hence considered a risk factor (Zhuang et al., 2016). The effect of ACE on angiotensin I (inactive decapeptide) converts it into angiotensin II (active octapeptide and potent vasoconstrictor) (Burrell et al., 2004). In a study on rats, angiotensin II injection by stimulation of angiotensin II type 1 receptors (AT1R) increased the expression of APP and BACE1 as well as the activity of β and γ secretase, causing the production of Aβ (Zhu et al., 2011); it significantly increased the phosphorylated tau levels via GSK 3β and other tau kinases too (Tian et al., 2012). In the AD mouse model, it has been observed that angiotensin II, AT1R ligand, increased Aβ production, PS1 endocleavage, and the formation of γ-secretase complex. In these mice, defects in the AT1R significantly reduced the production of Aβ and the formation of amyloid plaques. Moreover, in the absence of AT1R, the endocleavage of PS1, which is essential for the formation of γ-secretase complex and production of Aβ, is inhibited (Liu et al., 2015). The angiotensin receptor blockers in AD patients were observed to reduce the total and phosphorylated tau (Hajjar and Levey, 2015). The effects of olmesartan, as an angiotensin receptor antagonist, were evaluated in cerebrovascular dysfunction and cognitive impairment induced by Aβ in the AD mouse model. It was discovered that olmesartan decreased OxS in brain microvessels and significantly improved cognitive function; furthermore, impairment of hippocampal synaptic plasticity was decreased in these mice (Takeda et al., 2009). ACE2 is another type of angiotensin-converting enzyme that affects both, angiotensin I and angiotensin II, but its effect on angiotensin II is more pronounced than angiotensin I. The ACE2 converts angiotensin II to angiotensin 1–7 (cardioprotective peptide with vasodilator) (Burrell et al., 2004), significantly reducing its activity in AD. Furthermore, a negative correlation has been reported between the ACE2 level and levels of Aβ and phosphorylated tau. In addition, the activity of ACE2 has an inverse correlation to ACE activity with the ratio of ACE to ACE2 showing a significant increase in AD; consequently, the ratio of angiotensin II to angiotensin 1–7 is elevated too (Kehoe et al., 2016). In a study on mice, it has been shown that with the removal of ACE2, SOD is reduced and the production of superoxide anion and expression of NADPH oxidase subunits in the hippocampus is increased. This is indicative of oxidative stress. Moreover, it is reported that AT1R mRNA levels in the hippocampus increase and these mice showed a significant cognitive function impairment (Wang et al., 2016). In the sporadic AD mouse model, it has been shown that angiotensin 1–7 levels in the brain significantly

4. Alzheimer's drugs The US Food and Drug Administration (FDA) has affirmed a few drugs for AD therapy, which only ameliorate some symptoms of the disease, such as memory loss. These drugs have no effect on the progression of the disease or its prevention. The FDA-approved medications include acetylcholinesterase (AChE) inhibitors (rivastigmine, donepezil, and galantamine) and NMDAR antagonists (memantine). In recent years, medications with different mechanisms have been introduced for the treatment of AD, some of which have failed in clinical trials and others are still undergoing clinical trials. Some of these important therapeutic approaches in the clinical trial phase include AChE inhibitors, NMDAR's antagonists, therapies against Aβ, inhibition of TNF-α release and Glucagon-like peptide-1 (GLP-1) receptor agonist, which apelin may be able to do with similar mechanisms in the treatment of AD. 4.1. AChE inhibitors Acetylcholine (ACh) is an essential neurotransmitter needed for processing memory and learning. In patients suffering from AD, this neurotransmitter has a reduced concentration and function. This is caused due to the AChE activity degrading ACh to decrease its

Fig. 4. Apelin can prevent the production of amyloid beta and tau, inducing factors of Alzheimer's, by inhibiting angiotensin II signaling and, on the other hand, increase the ACE2 and convert angiotensin II to angiotensin 1–7 that can improve Memory and cognitive function. 6

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Fig. 5. Different Therapeutic Strategies in Alzheimer's disease. Apelin may be effective in treating Alzheimer's through most of these mechanisms. eNO: endothelial nitric oxide, Aβ: amyloid beta, ACh: acetylcholine, AChE: acetylcholinesterase, NMDAR: N-methyl Daspartate receptor, GSK: glycogen synthase kinase, NEP: Neprilysin, RAGE: receptor for advanced glycation end products, GLP-1: Glucagon-like peptide-1

concentration, thereby disrupting the memory and learning processes. AChE plays a role in the production of Aβ and its deposition too (Blokland, 1995; Talesa, 2001). Therefore, AChE inhibition is an effective therapeutic strategy for AD. Rivastigmine, donepezil, and galantamine are three FDA-approved drugs for AD that inhibit AChE, thereby improving memory and certain other symptoms of the disease (Godyń et al., 2016). NO is an important factor in regulating neurotransmitter secretion in the brain and is shown to increase ACh release (Prast and Philippu, 2001). Therefore, apelin may indirectly increase the release of ACh by increasing NO production (Ashley et al., 2006; Tatemoto et al., 2001a).

immunotherapy. Most of these strategies have failed in clinical trials while some are still undergoing clinical trials (Han and Mook-Jung, 2014). Apelin may be able to indirectly block the BACE1 activity and inhibit the conversion of APP to Aβ by increasing the production of eNO; moreover, it may increase the Aβ clearance through RAGE modulation and increasing LRP-1 (Katusic and Austin, 2013). It has also been observed that apelin, by increasing the levels of ABCA1 and NEP activity, and decreasing the BACE1 activity, reduced the amount of Aβ in vivo and in vitro (Xinping, 2014).

4.2. NMDAR antagonists

TNF-α is an inflammatory cytokine that is elevated in AD and contributes to neurodegeneration. It has been shown that thalidomide and its analogues in rat models can reduce TNF-α and prevent cognitive deficits. Thalidomide was subjected to a clinical trial in AD patients in 2010, but its results have not been disclosed yet (Godyń et al., 2016). Various studies have shown that apelin is an anti-inflammatory agent that reduces not only TNF-α but also other inflammatory mediators such as IL-1 and IL-6 (Chen et al., 2015a; Leeper et al., 2009).

4.4. Inhibition of TNF-α release

NMDAR-mediated excitotoxicity is an essential parameter in pathogenesis of AD that causes the death of neurons. Therefore, inhibiting NMDARs is a good therapeutic strategy for AD. memantine is the only NMDAR inhibitor that has been approved by the FDA. memantine, in addition to preventing the death of neurons by excitotoxicity, also reduces the hyperphosphorylation of tau protein (Lipton, 2006; Song et al., 2008). It has been shown that apelin can reduce the excitotoxicity induced by NMDARs and QUIN and prevent excitotoxicity-mediated neuronal death. Furthermore, it is possible that apelin can reduce the tau hyperphosphorylation by inhibiting calpain and QUIN (Cook et al., 2011; O'Donnell et al., 2007).

4.5. Glucagon-like peptide-1 receptor agonist GLP-1 is a major endogenous insulin tropic peptide that is released in response to food from the L cells of the gastrointestinal tract. It has been observed that the GLP-1 receptor agonist in the APP/PS1 transgenic mouse model of AD reduces the level of Bax and increases the levels of Bcl-2 and brain-derived neurotropic factor (BDNF), a key growth factor in protecting synaptic function. It also reduces total Aβ, neuroinflammation, and OxS in the cortex and hippocampus (Tai et al., 2018). GLP-1 has been able to reduce levels of brain Aβ in vivo and APP

4.3. Therapies against Aβ The potential strategies for targeting Aβ in AD treatment include inhibiting Aβ production by β and γ-secretase inhibition and APP modulation, degradation of Aβ by activating NEP, and Aβ removal via 7

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levels in cultured neurons (Perry et al., 2003). GLP-1 also protects the rat's hippocampal cultured neurons against glutamate-induced apoptosis (Perry et al., 2002). Therefore, GLP-1 can be a therapeutic strategy in AD treatment. In the mouse model of tauopathy, it has been shown that the GLP-1 receptor agonist, liraglutide, reduces tau pathology and phosphorylated tau accumulation (Hansen et al., 2016). Liraglutide is currently undergoing a clinical trial (ClinicalTrials.gov Identifier: NCT01843075) in patients with mild AD, which began in 2014, but its results have not yet been reported. It has been shown that on using the murine enteroendocrine cell line (STC-1), apelin-13 increases the GLP-1 secretion up to seven-fold in a dose-dependent manner. In addition, intravenous infusion of apelin-13 to adult rats, in dose-dependent manner, increased GLP-1 secretion in the portal blood (Wattez et al., 2013). It has been shown that in dietinduced obese mice, treatment with apelin-13 analogues elevated GLP1 levels (Parthsarathy et al., 2017). Other therapeutic strategies for AD include inhibition of GSK-3β signaling, RAGE, histamine H3 receptors, 5-hydroxytryptamine 6 receptors, and calcium channels (Godyń et al., 2016; Kumar and Singh, 2015) (Fig. 5).

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Costimulatory effects of interferon-γ and interleukin1β or tumor necrosis factor α on the synthesis of Aβ1-40 and Aβ1-42 by human astrocytes. Neurobiol. Dis. 7, 682–689. Blokland, A., 1995. Acetylcholine: a neurotransmitter for learning and memory? Brain Res. Rev. 21, 285–300. Blum-Degena, D., Müller, T., Kuhn, W., Gerlach, M., Przuntek, H., Riederer, P., 1995. Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci. Lett. 202, 17–20. Bodineau, L., Taveau, C., Lê Quan Sang, H.-H., Osterstock, G., Queguiner, I., Moos, F., Frugiere, A., Llorens-Cortes, C., 2011. Data supporting a new physiological role for brain apelin in the regulation of hypothalamic oxytocin neurons in lactating rats. Endocrinology 152, 3492–3503. Bon, C.L., Garthwaite, J., 2003. On the role of nitric oxide in hippocampal long-term potentiation. J. Neurosci. 23, 1941–1948. 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5. Conclusions Recent studies provide evidence for the hypothesis that apelin neuropeptide can be considered as an effective and comprehensive therapeutic agent in AD, which, unlike current therapies, can affect a higher number of mechanisms involved in AD pathogenesis. In relation to Aβ, apelin can reduce the production of Aβ by decreasing the amount of APP and decreasing the activity of β-secretase, and by increasing the levels of ABCA1 and increasing the activity of NEP, can lead to degradation of Aβ and reduce its accumulation. Apelin may be able to reduce phosphorylation and accumulation of tau protein. Apelin can prevent neurodegeneration by reducing the levels of inflammatory mediators, especially TNF-α and IL-1β, which plays an important role in the pathogenesis of AD. Apelin can modulate NMDARs and thus reduce excitotoxicity and death of neurons. In relation to apoptosis, an active process in neurodegeneration, apelin can prevent neuronal apoptosis by increasing the anti-apoptotic factors and reducing pro-apoptotic factors. Moreover, the high antioxidant effects of apelin can prevent the production of ROS and free radicals, apart from preventing oxidative damage to neurons. Apelin can increase the synaptic plasticity in the neurons, and improve memory and cognitive function by increasing some factors such as eNO, ACE2, and GLP-1. Given these properties, it is suggested that apelin can be an effective agent in the treatment of AD. Therefore, further investigation of the effects of apelin on the brain and its relationship with factors involved in the pathogenesis of AD is suggested. References Adamec, E., Mohan, P., Vonsattel, J.P., Nixon, R.A., 2002. Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2. Acta Neuropathol. 104, 92–104. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., 2000. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421. Albin, R.L., Greenamyre, J.T., 1992. Alternative excitotoxic hypotheses. Neurology 42, 733. Ashley, E.A., Powers, J., Chen, M., Kundu, R., Finsterbach, T., Caffarelli, A., Deng, A., Eichhorn, J., Mahajan, R., Agrawal, R., 2005. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc. Res. 65, 73–82. Ashley, E., Chun, H.J., Quertermous, T., 2006. Opposing cardiovascular roles for the angiotensin and apelin signaling pathways. J. Mol. Cell. Cardiol. 41, 778–781. Attané, C., Foussal, C., Le Gonidec, S., Benani, A., Daviaud, D., Wanecq, E., Guzmán-Ruiz, R., Dray, C., Bezaire, V., Rancoule, C., 2012. Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 61, 310–320. Austin, S.A., Santhanam, A.V., Katusic, Z.S., 2010. Endothelial nitric oxide modulates expression and processing of amyloid precursor protein novelty and significance.

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