Pathological impacts of chronic hypoxia on Alzheimer's disease - ACS

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Pathological impacts of chronic hypoxia on Alzheimer’s disease Feng Zhang, Long Niu, Song Li, and Weidong Le ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00442 • Publication Date (Web): 09 Nov 2018 Downloaded from http://pubs.acs.org on November 10, 2018

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ACS Chemical Neuroscience

Pathological impacts of chronic hypoxia on Alzheimer’s disease

Feng Zhang1, 2, Long Niu1, 2, Song Li1, 2, Weidong Le1, 2, *

1

Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China;

2

Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China.

*Corresponding author. Email: [email protected]; Tel/Fax: +86-411-8813-5850

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ABSTRACT Chronic hypoxia is considered as one of the important environmental factors contributing to the pathogenesis of Alzheimer’s disease (AD). Many chronic hypoxia-causing comorbidities, such as obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD), have been reported to be closely associated with AD. Increasing evidence has documented that chronic hypoxia may affect many pathological aspects of AD including amyloid β (Aβ) metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial and synaptic dysfunction, which may collectively result in neuron degeneration in the brain. In this review, we briefly summarized the effects of chronic hypoxia on AD pathogenesis and discussed the underlying mechanisms. Since chronic hypoxia is common in the elderly and may contribute to the pathogenesis of AD, prospective prevention and treatment targeting hypoxia may be helpful to delay or alleviate AD.

Key words: Chronic hypoxia, Alzheimer’s disease, amyloid β, tau, autophagy, neuroinflammation


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INTRODUCTION Alzheimer’s disease (AD) is pathologically featured by amyloid β (Aβ) deposition, abnormal tau phosphorylation and neuronal loss in the brain. It is generally considered that the pathogenesis of AD is related to genetic and non-genetic factors. Genetic factors include dominantly inherited mutations in Aβ precursor protein (APP), presenilin 1, and presenilin 2 (PSEN2), which cause mostly early onset AD, and risk genes associated with familial and sporadic AD, including apolipoprotein E, a disintegrin and metalloproteinase 10, clusterin, ATP-binding cassette transporter, bridging integrator protein 1, and others1. Despite these AD-related genes, only a small proportion (95%) are sporadic AD2, which is considered as the consequence of interactions between genetic risk and non-genetic factors3. There are several major non-genetic factors such as cerebrovascular diseases, type 2 diabetes, brain trauma, intellectual activity, hypoxia, sleep disorders, and others, which may contribute to the disease onset and progression4. Thus, it becomes increasingly interesting to identify disease-causing environmental factors. Hypoxia is a reduction of oxygen supply caused by cardiovascular problems hematological diseases, respiratory dysfunction, medications, or environmental conditions, which affect the functions of organs, especially the central nervous system. Stroke or acute cerebral ischemia can result in acute hypoxic condition, whereas chronic respiratory disease and sleep-disordered breathing can cause chronic hypoxia5. It has been reported that hypoxia is associated with the familial and sporadic AD6-8. Chronic hypoxia, especially chronic intermittent hypoxia with repeated exposure to low oxygen and reoxygenation may have deleterious effects on AD pathogenesis, whereas acute preconditioned hypoxia may



have protective effects in cardiovascular and nervous system9. Previous studies from our center and other institutions have demonstrated that hypoxia can increase Aβ production10, enhance tau phosphorylation11, induce neuroinflammation12, increase reactive oxygen species (ROS) generation7, and elicit abnormal mitochondrial function5. Studies have also shown the deleterious effects of high-altitude hypoxia exposure on cognitive performance13, 14.

High altitude decreases brain oxygen saturation, reduces neural activity, impairs

cognitive functions, and induces immune response15. High altitude hypoxia also suppresses the training-dependent cognitive advantages, which is associated with decreased brainderived neurotrophic factor (BDNF) and elevated inflammatory factor during hypoxia exposure16. A study of 24-hour hypoxia exposure in a normobaric chamber showed that hypoxia impairs cognitive function, mood, and sleep pattern17. Another study in children who lived at a high altitude with long-term exposure to hypoxia showed that chronic hypoxia might lead to impairment of their learning abilities14. Clinical AD patients suffering from slowly progressive cognitive decline may have co-morbidities of repeated chronic hypoxic condition, such as obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD)18, 19. A prospective study of 298 women reported that women with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia, implying that chronic hypoxia may contribute to the pathogenesis of AD and related diseases20. In this review, we briefly summarized the effects of chronic hypoxia on AD-related pathologies, including Aβ metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, mitochondrial and synaptic dysfunction, and ER stress. A better understanding of the mechanisms of chronic hypoxia in AD pathogenesis will provide useful information for AD prevention and therapeutics.


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Chronic hypoxia and amyloid β Aβ is the main component of senile plaques deposited in the AD brain, which is derived from sequential cleavages of APP protein by β- and γ-secretase21. Various different Aβ species are produced after γ-secretase-mediated cleavage. Aβ40 (about 80-90%) is the most abundant form of Aβ, whereas Aβ42 (about 5-10%) as principal form deposited in AD brain is more hydrophobic and fibrillogenic and is more prone to the synaptic damage, neuritic injury and neuronal death22. Studies have demonstrated that chronic hypoxia may play a role in Aβ metabolism. Firstly, chronic hypoxia promotes the production of Aβ10, 23. Our previous study showed that 60-day chronic hypoxia treatment increased the levels of detergent soluble Aβ42 and formic acid soluble Aβ42 in mice and consequently increased senile plaques formation10. Furthermore, the level of anterior pharynx-defective 1α (APH-1α), a component of γsecretase, and the ratio of C99/C83, which were carboxyterminal fragments after cleavage of β- or α-secretase respectively, was increased in hypoxic mice, indicating an increased β- and γ-cleavage of APP10. A chronic intermittent hypoxia study also reported a significant increase of Aβ42 level and an increased intracellular Aβ staining in the brain cortex24. Another study demonstrated that chronic hypoxia could up-regulate the activity of β-site APP cleaving enzyme 1 (BACE1), facilitate β-cleavage of APP, increase Aβ deposition and potentiate the memory deficit in hypoxia-exposed APP23 transgenic AD mice25. The up-regulation of BACE1 might be resulted from hypoxia-regulated transcription factors, such as hypoxia inducible factor-1 (HIF-1), binding to hypoxia-responsive element site in the promoter region of BACE1 gene25, 26. Recently, our study showed that chronic hypoxia



increased senile plaques deposition, elevated the ratio of Aβ42/Aβ40, and finally caused learning and memory deficits in hypoxia-treated APPswe/PS1dE9 mice23. Moreover, chronic hypoxia increased the protein levels of BACE1 and components of γ-secretase including APH1a, presenilin enhancer 2 (PEN2), and nicastrin (NCSTN) in hypoxic mice23. More interestingly, the genome DNA methylation and methylation levels of CpG sites in promoter regions of presenilin1 (PS1), PEN2, and NCSTN genes were decreased in hypoxic mice, with reduced protein level of DNA methyltransferase 3b, indicating that the changes of components of γ-secretase might result from epigenetic modifications23. Furthermore, a two-vessel occlusion rat model study found that microRNA-9 increased BACE1 expression via downregulation of c-AMP response element-binding protein (CREB) under chronic hypoxia condition27, which provided another evidence that chronic hypoxia could regulate APP-processing secretases through epigenetic modification. Secondly, chronic hypoxia is reported to be associated with declined degradation and clearance of Aβ23, 28. Neprilysin (NEP) is one of the major enzymes responsible for Aβ degradation. It was demonstrated that chronic hypoxia down-regulated NEP level in AD mice23, and the protein and mRNA levels of NEP were both decreased under hypoxic condition in vitro29. Furthermore, the down-regulation of NEP was reported to be associated with histone methylation and deacetylation29. Dimethylation of histone H3 lysine 9 (H3K9me2) is a critical marker for DNA methylation and gene silencing, whereas H3-K4 trimethylation (H3K4me3) is involved in gene activation30. It was reported that H3K9me2 levels in the NEP promoter regions were significantly increased whereas H3K4me3 was partly diminished in the cultures of cortical and hippocampal neurons under hypoxic condition29. Hypoxia was also found to suppress NEP expression through histone


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deacetylation29, which might be involved in gene silencing30. The main receptors for the clearance of Aβ across the blood-brain barrier (BBB) and Aβ influx from blood to brain are low-density lipoprotein receptor related protein-1 (LRP-1) and receptor for advanced glycation end products (RAGE), respectively31. A study using bilateral common carotid artery occlusion (BCCAO) model showed that chronic cerebral hypoperfusion caused the increase of hippocampal RAGE and decrease of LRP-1 together with BBB damage and impaired Aβ transport and clearance in BCCAO mice28. Chronic cerebral hypoperfusioninduced heparin-binding EGF-like growth factor expression increased HIF-1α, generated matrix metalloprotease-9 and further stimulated BBB disintegration28.

Besides, studies on human participants have also indicated an association between chronic hypoxia and AD. One study showed that OSAS patients exhibited significant higher serum Aβ40, Aβ42 and total Aβ levels when compared to simple snoring control subjects (not OSAS)32. All of these Aβ levels were positively correlated with the apneahypopnea index, the oxygen desaturation index, and the mean and lowest oxyhemoglobin saturations32. Another study reported that OSA children had significant elevations in both Aβ42 and PS1 circulating levels33. Moreover, OSA children after adenotonsillectomy resulted in significant reductions of Aβ42 and PS1 levels33. The results from these studies suggested that chronic hypoxia resulted from OSAS was associated with AD-related pathogenesis and might accelerate AD-related processes even in early childhood32, 33. In addition, AD patients with OSAS often had cerebral vessel functional and structural alterations, and the extent of cerebrovascular impairment was correlated with the severity of OSAS, implying that OSAS might contribute to vascular impairments in AD patients34.

Chronic hypoxia and tau



Tau is a microtubule associated protein mainly concentrated in axons. It binds to microtubules, stabilizes their structure, and may have alternative functions in axonal transport and synapsis35. Under pathological conditions, hyperphosphorylated tau dissociates from the microtubules and self-associates to form prefibrillar oligomeric and fibrillar aggregates known as paired helical filaments and neurofibrillary tangles (NFTs)36. NFTs is one of the pathological hallmarks of AD and several other neurodegenerative diseases37. Hyperphosphorylation of tau is caused by dysregulation of kinases and phosphatases, including glycogen synthase kinase-3β (GSK-3β), cyclin-dependent-like kinase-5 (CDK5) and protein phosphatase 2A (PP2A)38, 39. Several studies have reported that chronic hypoxia could enhance tau phosphorylation11, 40.

A study on rat showed that chronic hypoxia (4-8 weeks) increased tau phosphorylation

at Ser198/199/202, Thr205, Ser262, Ser396 and Ser404 in the hippocampus and caused spatial memory deficit40. Besides, the levels of Tyr216-phosphorylated GSK-3β (activated form) and Tyr307-phosphorylated PP2A (inactivated form) were significantly increased, while the level of methylated PP2A (activated form) were significantly decreased in the hippocampus after chronic hypoxia exposure40. Another study showed that chronic hypoxia treatment increased tau phosphorylation at Ser396, Ser205, and Thr231, which was associated with significantly increased levels of p35 and p25 together with an upregulated calpain, suggesting that chronic hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain11. Chronic hypoxia may up-regulate protein kinases, including GSK-3β and CDK5, and suppress phosphatase, PP2A, leading to an enhanced tau phosphorylation11, 40. A study using unilateral common carotid artery occlusion model demonstrated that chronic cerebral hypoperfusion induced tau phosphorylation at


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Ser199/202 in young and aged AD mice and in aged wild type (WT) mice, indicating that chronic hypoxia or hypoperfusion could enhance tau phosphorylation with or without genetic factors41. Similarly, a study on WT C57BL/6J mice also showed that 28-day intermittent hypoxia increased tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr212, Ser214, Thr231, Ser396, Ser400, and Ser40442. Gene ontology-based microarray analysis revealed common biological processes between intermittent hypoxia treatment and aging42. These results in WT mice implied that chronic hypoxia might be an important contributor to promote tau phosphorylation in sporadic AD. Study on human participants also showed the correlation between chronic hypoxia and tau pathology. It was reported that OSAS patients exhibited strikingly higher level of serum phosphorylated tau Thr181 when compared to simple snoring subjects, and these levels were positively correlated with serum Aβ level32.

Chronic hypoxia and autophagy Autophagy or macroautophagy is a cellular process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. It is essential to clear toxic or aggregated proteins and dysfunctional or damaged organelles such as mitochondria43. It is reported that autophagy in microglia degrades extracellular Aβ fibrils44 and that the autophagy-lysosome system degrades tau protein in various forms45. Electron microscopy studies identified an accumulation of autophagosomes in different autophagic stages in AD brain, implying that autophagic degradation system might be compromised in AD46. It was also reported that PS1 was essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Lysosomal proteolysis and autophagy



could be disrupted by AD-related PS1 mutations47. Autophagic dysfunction is reported to be involved in hypoxia-mediated pathogenesis of AD48. A recent study found that chronic hypoxia activated autophagy and impaired autophagic flux in AD mouse brain with a large amount of autophagic vacuole accumulation and significant high level of p62, a selective autophagy receptor for degradation of ubiquitinated substrates48. Activation of AMP-activated protein kinase further inhibited mechanistic target of rapamycin activity resulting in activation of autophagy48. Moreover, this study also showed that hypoxia-induced autophagy significantly elevated the level of human Aβ4248. Hypoxia-induced autophagic activation might lead to the aggregation of C99 and accumulation of autophagic vacuoles, in which C99 was further cleaved by γ-secretase to yield Aβ over-production10. Another study reported that two-vessel occlusion rat model of chronic cerebral hypoperfusion showed increased number of LC3- and beclin1-positive autophagosomes and decreased protein level of mTOR along with increased level of microRNA-9649. Inhibition of microRNA-96 decreased LC3- and beclin1-positive autophagosomes and increased protein level of mTOR, indicating the critical role of microRNA in the regulation of autophagy under hypoxic condition49.

Chronic hypoxia and neuroinflammation Neuroinflammation is thought to be another important pathological mechanism contributing to the pathogenesis of AD50. Besides their neurotoxicity, Aβ and tau can also activate immune response, resulting in secretion of pro-inflammatory cytokines, chemokines, neurotoxins including reactive oxygen species (ROS) and nitric oxide (NO),


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and excitatory amino acids, which can further lead to neurodegeneration50. Although immune response is intended to be protective, excessive inflammatory response may cause neuronal damage and degeneration50. One previous study showed that 1-, 3-, 14-day of intermittent hypoxia time-dependently increased cyclooxygenase-2 (COX-2), interleukin 1β (IL-1β), and IL-6 mRNA levels in cortical microglia with the peak expression in 14-day intermittent hypoxia51. Changes of COX-2, IL-1β, and IL-6 mRNA levels in medullary microglia were early and long-lasting in all 1-, 3-, 14-day intermittent hypoxia51. The mRNA level of toll-like receptor 4 (TLR4), a type-I transmembrane receptor involved in microglial inflammatory response, was increased in cortical and brain stem with timing of peak inflammatory gene expression, suggesting

that

TLR4

might

play

a

role

in

intermittent

hypoxia-induced

neuroinflammation51. These results suggested that different brain regions might have different vulnerability to intermittent hypoxia. Another study reported that chronic intermittent hypoxia, but not acute intermittent hypoxia induced significant microglial changes in dorsal hippocampus, including increased density and morphological features of microglia priming51. Acute intermittent hypoxia but not chronic intermittent hypoxia increased IL-1β and chemokine C-C motif ligand 5 mRNA levels in dorsal hippocampus51. Chronic intermittent hypoxia plus lipopolysaccharide increased IL-6 and IL10 mRNA whereas lipopolysaccharide alone did not affect these cytokines51. These results indicated that hypoxia might affect neuroinflammation in CNS in a time- and region-specific manner. Microglia from chronic hypoxia-treated APP/PS1 AD mice exhibited marked reduction in expression of cluster of differentiation 36 (CD36), a class B scavenger receptor, and decreased expression of Aβ-degrading enzymes, including insulin degradation enzyme,



NEP, and matrix metalloproteinase-952. The reduction of CD36 expression and Aβ degradation was associated with the attenuation of nuclear factor erythroid 2-related factor 2 signaling under chronic hypoxic condition52.

Chronic hypoxia and oxidative stress Oxidative stress is a disturbance in the balance between the production of ROS and antioxidant defenses53. Accumulating evidence has shown that the presence of extensive oxidative stress is a characteristic of AD brains54. The levels of products of protein oxidation, such as protein carbonyls and 3-nitrotyrosine, markers of oxidative damage to DNA and RNA, such as 8-hydroxydeoxyguanosine (8-OHdG) and 8-hydroxyguanosine, and products of lipid peroxidation, such as malondialdehyde, 4-hydroxynonenal, and F2isoprostanes, were found significantly higher in AD brains55. A study reported that chronic intermittent hypoxia increased advanced oxidative protein products levels in plasma of rats exposed to chronic intermittent hypoxia when compared to controls and the expression of 8-OHdG was elevated in entorhinal cortex and hippocampus in chronic intermittent hypoxia rats56. Hypoxia-induced ROS production is believed to contribute to hypoxiamediated up-regulation of BACE1 expression, but this up-regulation occurs in a biphasic manner, through two distinct mechanisms. The early induction of BACE1 could be mediated by production of ROS, but the late augmentation of BACE1 is consistent with the activation of the HIF1α57. In addition, hypoxia can induce the release of vascular endothelial growth factor (VEGF) and HIF-1 by endothelial cells to promote neovascularization. However, excessive ROS production that is out-weighted by the amount and duration of oxidation may result in deficient vascular response and impaired


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neovascularization, which may lead to intra-plaque hemorrhages, erythrocyte lysis, and iron ion deposition and in return increase oxidation stress58.

Chronic hypoxia and mitochondrial dysfunction Mitochondria are the major source of cellular energy and regulate intracellular calcium levels and survival pathways59. It has been shown that mitochondrial function are impaired in AD brain, with reduced membrane potential, increased permeability, and excessive ROS production, which is believed to contribute to the neurodegeneration60. Impaired enzyme complexes in tricarboxylic acid cycle and reduced respiratory chain complexes have been documented in AD brain59. A hypobaric hypoxia study demonstrated that 28-day hypoxia induced alteration of mitochondrial morphology, impaired mitochondrial function caused excessive mitochondrial fission and decreased mitochondrial fusion, as evidenced by small, fragmented mitochondria and reduced mitochondrial density in neuronal processes in rat hippocampus61. Another study reported that chronic hypoxia altered mitochondrial morphology, disruption of cristae, and led to lipofuscin aggregation in CA3 region of hippocampus62. Furthermore, mitochondrion-derived ROS was reported to enhance amyloidogenic APP processing leading to excessive Aβ formation, which could be attenuated by ROS scavenging using the antioxidant vitamin C63. On the other hand, Aβ can be translocated into mitochondria, interacted with mitochondrial proteins and disturb energy production64. Mitochondria dysfunction in return causes release of mitochondrial proteins, such as cytochrome c, and triggers apoptosis leading to the degeneration of neurons65.



Chronic hypoxia and synaptic dysfunction Synapses are the fundamental units of information transfer and storage in the brain, composed of pre- and postsynaptic compartments66. Neuronal death and synaptic degeneration lead to the collapse of neural networks and further cause memory and cognition impairment. In AD, synapse loss is observed in frontal cortex, temporal cortex, and dentate gyrus of the hippocampus67. Altered synaptic plasticity and dysregulated mechanisms involved in normal plasticity lead to synapse dysfunction and collapse67. In a recent study, chronic hypoxia decreased the density of synapses in the hippocampus under electron microscope and decreased the protein level of synaptophysin, a synaptic vesicle glycoprotein, in both Wt and AD mice, indicating that chronic hypoxia could result in synapse loss23. It is reported that chronic intermittent hypoxia could depress afferent neurotransmission in the nucleus of the solitary tract by reducing the number of active synapses68. Chronic intermittent hypoxia could impair both early- and late-phase long-term potentiation in the hippocampus along with reduced level of hippocampal brain-derived neurotrophic factor, indicating that chronic intermittent hypoxia could cause defect in longterm synaptic plasticity69. Under hypoxic condition, increased ionotropic receptor stimulation by glutamate could lead to calcium-mediated excitotoxic cell death. Therapeutics upregulating glial glutamate transporter, which was responsible for the clearance of glutamate from the synapse, were reported to rescue hippocampal neurons from excitotoxicity and enhance cognitive function under chronic hypobaric hypoxia70.

Chronic hypoxia and endoplasmic reticulum stress A number of pathophysiological insults, including hypoxia, nutrient deprivation, etc., lead


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to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress71. In response to accumulation of unfolded/misfolded proteins, cells adapt the unfolded protein response (UPR) to the stress condition, such as attenuation of general translation and activation of ER-associated degradation to eliminate immature proteins72. A study reported that 2-month hypoxia increased the UPR, upregulated apoptotic signaling, enhanced the activation of GSK3β, and increased tau hyperphosphorylation and Aβ deposition in APP/PS1 AD mice73. Silencing of m-calpain reduced hypoxia-induced cellular

dysfunction

and

suppressed

GSK3β

activation,

ER

stress,

tau

hyperphosphorylation, and caspase pathway73. The results suggested that hypoxiatriggered m-calpain activation was involved in ER stress-mediated AD pathogenesis73. Mutation of PEN2 gene might contribute to the suppression of the UPR and stimulate γsecretase activity under hypoxia condition74.

Prospective strategies targeting on chronic hypoxia to prevent and treat AD Since chronic hypoxia is involved in AD pathogenesis, prevention and treatments targeting hypoxia may be helpful to delay or ameliorate the progression of AD, especially in patients with hypoxic conditions. Hyperbaric oxygen therapy (HBOT) is widely used in medical practice in which oxygen is the rate-limiting factor for tissue recovery. It is reported that HBOT can improve cognitive behavioral performance, reduce Aβ load and tau hyperphosphorylation, and alleviate neuroinflammation by reducing astrogliosis and microgliosis, decreasing proinflammatory cytokines and elevating phagocytic markers in 3xTg AD mice75. HBOT pretreatment can also lower the rates of neuronal damage, astrocyte activation, dendritic spine loss, and hippocampal neuron apoptosis in a rat model



injected Aβ40, with a lower rate of hippocampal p38 mitogen-activated protein kinase phosphorylation76. Moreover, HBOT was shown to inhibit Aβ25-35-induced toxicity and oxidative stress77, and reduce apoptosis with nuclear factor-κB pathway activation in AD rats78. These animal studies have shown that HBOT might be a promising strategy for the treatment of AD. For patients with chronic respiratory disease and sleep-disordered breathing, adenotonsillectomy or treatment of comorbidities that helps to ameliorate chronic hypoxia condition might be helpful to prevent cognitive impairment or delay AD progression.

SUMMARY Chronic hypoxia is one of the important environmental factors contributing to the pathogenesis of AD. As mentioned above, it may affect many pathogenetic aspects including Aβ metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, mitochondrial and synaptic dysfunction, and ER stress (Fig. 1), which can directly or indirectly cause neuron degeneration. Brain cells with high demand on metabolic activity, especially in hippocampus and cortex, are susceptible to hypoxic conditions79, 80. Previous study reported that chronic hypoxia could induce neuron apoptosis in CA1 region of hippocampus81, indicating that chronic hypoxia could cause neuronal loss in hypoxiavulnerable brain areas. More interestingly, chronic hypoxia not only aggravates AD-related pathologies and cognitive decline in AD mice but also in WT mice to certain extent, implying that chronic hypoxia may affect people with genetic predispositions as well as people without them23,

42.

Considering that chronic hypoxia is a common risk factor

contributing to the pathogenesis of AD, prospective prevention and treatment targeting


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hypoxia might be helpful to delay or alleviate AD.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Weidong Le: 0000-0001-7459-2705

ACKNOWLEDGMENTS This work was supported in part by funding from the National Natural Sciences Foundation of China (NSFC 81430021 and 81771521).

AUTHOR CONTRIBUTIONS W.L. conceived the structure of the review. F.Z., L.N. and S.L. performed literature searches and wrote the manuscript. F.Z., L.N., S.L. and W.L. revised the manuscript.



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FIGURE LEGEND Figure 1. Chronic hypoxia affects amyloid β (Aβ) metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, mitochondrial and synaptic dysfunction, and endoplasmic reticulum (ER) stress in Alzheimer’s disease (AD).


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Table of Content Graphic Pathological impacts of chronic hypoxia on Alzheimer’s disease Feng Zhang, Long Niu, Song Li, Weidong Le

For Table of Contents Use Only



Figure 1. Chronic hypoxia affects amyloid β (Aβ) metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, mitochondrial and synaptic dysfunction, and endoplasmic reticulum (ER) stress in Alzheimer’s disease (AD).


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Pathological impacts of chronic hypoxia on Alzheimer's disease - ACS

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