Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer’s disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.
JahanshahiM, NikmahzarE, SayyahiA (2020) Vitamin E therapy prevents the accumulation of congophilic amyloid plaques and neurofibrillary tangles in the hippocampus in a rat model of Alzheimer’s disease. Iran J Basic Med Sci23, 86–92.
2.
CervellatiC, TrentiniA, PecorelliA, ValacchiG (2020) Inflammation in neurological disorders: The thin boundary between brain and periphery. Antioxid Redox Signal33, 191–210.
3.
AgnihotriA, AruomaOI (2020) Alzheimer’s disease and Parkinson’s disease: A nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals. J Am Coll Nutr39, 16–27.
4.
(2020) 2020 Alzheimer’s disease facts and figures. Alzheimers Dement16, 391–460.
5.
MullaneK, WilliamsM (2020) Alzheimer’s disease beyond amyloid: Can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery?Biochem Pharmacol177, 113945.
ChenR, LaiUH, ZhuL, SinghA, AhmedM, ForsythNR (2018) Reactive oxygen species formation in the brain at different oxygen levels: The role of hypoxia inducible factors. Front Cell Dev Biol6, 132.
8.
SunX, HeG, QingH, ZhouW, DobieF, CaiF, StaufenbielM, HuangLE, SongW (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A103, 18727–18732.
9.
LiuH, QiuH, YangJ, NiJ, LeW (2016) Chronic hypoxia facilitates Alzheimer’s disease through demethylation of gamma-secretase by down regulating DNA methyltransferase 3b. Alzheimers Dement12, 130–143.
10.
KerridgeC, KozlovaDI, NalivaevaNN, TurnerAJ (2015) Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism. Front Neurosci9, 426.
11.
MichelG, MinetE, ErnestI, RolandI, DurantF, RemacleJ, MichielsC (2000) A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its consensus DNA sequence. J Biomol Struct Dyn18, 169–179.
12.
Lavista-LlanosS, CentaninL, IrisarriM, RussoDM, GleadleJM, BoccaSN, MuzzopappaM, RatcliffePJ, WappnerP (2002) Control of the hypoxic response in Drosophila melanogaster by the helix-loop-helix PAS protein similar. Mol Cell Biol22, 6842–6853.
13.
ScheuermannTH, LiQ, MaHW, KeyJ, ZhangL, ChenR, GarciaJA, NaidooJ, LonggoodJ, FrantzDE, TambarUK, GardnerKH, BruickRK (2013) Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol9, 271–276.
14.
LeuT, SchutzholdV, FandreyJ, FerenzKB (2019) When the brain yearns for oxygen. Neurosignals27, 50–61.
15.
CristanteE, LiyanageSE, SampsonRD, KalargyrouA, De RossiG, RizziM, HokeJ, RibeiroJ, MaswoodRN, DuranY, MatsukiT, AghaizuND, LuhmannUF, SmithAJ, AliRR, BainbridgeJWB (2018) Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner. Development145, dev157511.
16.
IyalomheO, SwierczekS, EnweremN, ChenY, AdedejiMO, AllardJ, NtekimO, JohnsonS, HughesK, KurianP, ObisesanTO (2017) The role of hypoxia-inducible factor 1 in mild cognitive impairment. Cell Mol Neurobiol37, 969–977.
17.
KimS, LeeM, ChoiYK (2020) The role of a neurovascular signaling pathway involving hypoxia-inducible factor and notch in the function of the central nervous system. Biomol Ther (Seoul)28, 45–57.
18.
MerelliA, RodriguezJCG, FolchJ, RegueiroMR, CaminsA, LazarowskiA (2018) Understanding the role of hypoxia inducible factor during neurodegeneration for new therapeutics opportunities. Curr Neuropharmacol16, 1484–1498.
19.
SemenzaGL (2016) The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta1863, 382–391.
20.
XueL, ChenH, LuK, HuangJ, DuanH, ZhaoY (2017) Clinical significance of changes in serum neuroglobin and HIF-1alpha concentrations during the early-phase of acute ischemic stroke. J Neurol Sci375, 52–57.
21.
DuanC (2016) Hypoxia-inducible factor 3 biology: Complexities and emerging themes. Am J Physiol Cell Physiol310, C260–269.
22.
WoodSM, GleadleJM, PughCW, HankinsonO, RatcliffePJ (1996) The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in ARNT-deficient cells. J Biol Chem271, 15117–15123.
GaoS, LuL, BaiY, ZhangP, SongW, DuanC (2014) Structural and functional analysis of amphioxus HIFalpha reveals ancient features of the HIFalpha family. FASEB J28, 1880–1890.
25.
YangXS, YiTL, ZhangS, XuZW, YuZQ, SunHT, YangC, TuY, ChengSX (2017) Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury. Sci Rep7, 5818.
26.
DesmondDW, MoroneyJT, SanoM, SternY (2002) Incidence of dementia after ischemic stroke: Results of a longitudinal study. Stroke33, 2254–2260.
27.
SoucekT, CummingR, DarguschR, MaherP, SchubertD (2003) The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron39, 43–56.
28.
AminovaLR, ChavezJC, LeeJ, RyuH, KungA, LamannaJC, RatanRR (2005) Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line. J Biol Chem280, 3996–4003.
29.
BuscheMA, HymanBT (2020) Synergy between amyloid-beta and tau in Alzheimer’s disease. Nat Neurosci23, 1183–1193.
30.
MajdiA, Sadigh-EteghadS, Rahigh AghsanS, FarajdokhtF, VatandoustSM, NamvaranA, MahmoudiJ (2020) Amyloid-beta, tau, and the cholinergic system in Alzheimer’s disease: Seeking direction in a tangle of clues. Rev Neurosci31, 391–413.
31.
WangX, SunY, LiT, CaiY, HanY (2020) Amyloid-beta as a blood biomarker for Alzheimer’s disease: A review of recent literature. J Alzheimers Dis73, 819–832.
32.
RaoCV, AschAS, CarrDJJ, YamadaHY (2020) “Amyloid-beta accumulation cycle” as a prevention and/or therapy target for Alzheimer’s disease. Aging Cell19, e13109.
33.
NgKM, LauCF, FungML (2010) Melatonin reduces hippocampal beta-amyloid generation in rats exposed to chronic intermittent hypoxia. Brain Res1354, 163–171.
34.
GuglielmottoM, AragnoM, AutelliR, GilibertoL, NovoE, ColombattoS, DanniO, ParolaM, SmithMA, PerryG, TamagnoE, TabatonM (2009) The up-regulation of BACE1 mediated by hypoxia and ischemic injury: Role of oxidative stress and HIF1alpha. J Neurochem108, 1045–1056.
GuglielmottoM, TamagnoE, DanniO (2009) Oxidative stress and hypoxia contribute to Alzheimer’s disease pathogenesis: Two sides of the same coin. ScientificWorldJournal9, 781–791.
37.
SalminenA, KauppinenA, KaarnirantaK (2017) Hypoxia/ischemia activate processing of Amyloid Precursor Protein: Impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J Neurochem140, 536–549.
38.
De GasperiR, SosaMA, DrachevaS, ElderGA (2010) Presenilin-1 regulates induction of hypoxia inducible factor-1alpha: Altered activation by a mutation associated with familial Alzheimer’s disease. Mol Neurodegener5, 38.
39.
LiL, ZhangX, YangD, LuoG, ChenS, LeW (2009) Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging30, 1091–1098.
40.
WangR, ZhangYW, ZhangX, LiuR, HongS, XiaK, XiaJ, ZhangZ, XuH (2006) Transcriptional regulation of APH-1A and increased gamma-secretase cleavage of APP and Notch by HIF-1 and hypoxia. FASEB J20, 1275–1277.
41.
MarshallAJ, RattrayM, VaughanPF (2006) Chronic hypoxia in the human neuroblastoma SH-SY5Y causes reduced expression of the putative alpha-secretases, ADAM10 and TACE, without altering their mRNA levels. Brain Res1099, 18–24.
42.
WebsterNJ, GreenKN, PeersC, VaughanPF (2002) Altered processing of amyloid precursor protein in the human neuroblastoma SH-SY5Y by chronic hypoxia. J Neurochem83, 1262–1271.
43.
GrammasP, SamanyPG, ThirumangalakudiL (2006) Thrombin and inflammatory proteins are elevated in Alzheimer’s disease microvessels: Implications for disease pathogenesis. J Alzheimers Dis9, 51–58.
44.
Avramovich-TiroshY, Bar-AmO, AmitT, YoudimMB, WeinrebO (2010) Up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, M30. Curr Alzheimer Res7, 300–306.
OranskyI (2003) Oxygen sensor is neuroprotective in Alzheimer’s disease. Lancet Neurol2, 456.
47.
SchubertD, SoucekT, BlouwB (2009) The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide. Eur J Neurosci29, 1323–1334.
48.
CorreiaSC, MoreiraPI (2010) Hypoxia-inducible factor 1: A new hope to counteract neurodegeneration?J Neurochem112, 1–12.
49.
YangYT, JuTC, YangDI (2005) Induction of hypoxia inducible factor-1 attenuates metabolic insults induced by 3-nitropropionic acid in rat C6 glioma cells. J Neurochem93, 513–525.
50.
LeeKS, KimSR, ParkHS, ParkSJ, MinKH, LeeKY, ChoeYH, HongSH, HanHJ, LeeYR, KimJS, AtlasD, LeeYC (2007) A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha. Exp Mol Med39, 756–768.
51.
SiddiqA, AminovaLR, RatanRR (2007) Hypoxia inducible factor prolyl 4-hydroxylase enzymes: Center stage in the battle against hypoxia, metabolic compromise and oxidative stress. Neurochem Res32, 931–946.
52.
OgunsholaOO, AntoniouX (2009) Contribution of hypoxia to Alzheimer’s disease: Is HIF-1alpha a mediator of neurodegeneration?Cell Mol Life Sci66, 3555–3563.
53.
ShinR, IwakiT, KitamotoT, TateishiJ (1991) Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer’s disease brain tissues. Lab Invest64, 693–702.
54.
KistP, HastieI (1995) Alzheimer’s disease. Postgrad Med J71, 204–205.
55.
ChunW, JohnsonG (2007) The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci12, 733–756.
56.
IqbalK, Alonso AdelC, ChenS, ChohanMO, El-AkkadE, GongCX, KhatoonS, LiB, LiuF, RahmanA, TanimukaiH, Grundke-IqbalI (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta1739, 198–210.
NewcombeEA, Camats-PernaJ, SilvaML, ValmasN, HuatTJ, MedeirosR (2018) Inflammation: The link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation15, 276.
68.
RiesterK, BrawekB, SavitskaD, FrohlichN, ZirdumE, MojtahediN, HenekaMT, GaraschukO (2020) In vivo characterization of functional states of cortical microglia during peripheral inflammation. Brain Behav Immun87, 243–255.
69.
SubhramanyamCS, WangC, HuQ, DheenST (2019) Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin Cell Dev Biol94, 112–120.
70.
RegenF, Hellmann-RegenJ, CostantiniE, RealeM (2017) Neuroinflammation and Alzheimer’s disease: Implications for microglial activation. Curr Alzheimer Res14, 1140–1148.
71.
GeldersG, BaekelandtV, Vander PerrenA (2018) Linking neuroinflammation and neurodegeneration in Parkinson’s disease. J Immunol Res2018, 4784268.
72.
LoisC, GonzalezI, Izquierdo-GarciaD, ZurcherNR, WilkensP, LoggiaML, HookerJM, RosasHD (2018) Neuroinflammation in Huntington’s disease: New insights with (11)C-PBR28 PET/MRI. ACS Chem Neurosci9, 2563–2571.
73.
BjelobabaI, SavicD, LavrnjaI (2017) Multiple sclerosis and neuroinflammation: The overview of current and prospective therapies. Curr Pharm Des23, 693–730.
74.
Dudvarski StankovicN, TeodorczykM, PloenR, ZippF, SchmidtMHH (2016) Microglia-blood vessel interactions: A double-edged sword in brain pathologies. Acta Neuropathol131, 347–363.
75.
PatelNS, ParisD, MathuraV, QuadrosAN, CrawfordFC, MullanMJ (2005) Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J Neuroinflammation2, 9.
76.
BaikSH, KangS, LeeW, ChoiH, ChungS, KimJI, Mook-JungI (2019) A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab30, 493–507e496.
77.
ZhaoJ, O’ConnorT, VassarR (2011) The contribution of activated astrocytes to Abeta production: Implications for Alzheimer’s disease pathogenesis. J Neuroinflammation8, 150.
EbneterA, KokonaD, SchneiderN, ZinkernagelMS (2017) Microglia activation and recruitment of circulating macrophages during ischemic experimental branch retinal vein occlusion. Invest Ophthalmol Vis Sci58, 944–953.
80.
HuangT, HuangW, ZhangZ, YuL, XieC, ZhuD, PengZ, ChenJ (2014) Hypoxia-inducible factor-1alpha upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction. Neuroreport25, 1122–1128.
81.
YangZ, ZhaoTZ, ZouYJ, ZhangJH, FengH (2014) Hypoxia Induces autophagic cell death through hypoxia-inducible factor 1alpha in microglia. PLoS One9, e96509.
82.
de LemosML, de la TorreAV, PetrovD, BroxS, FolchJ, PallasM, LazarowskiA, Beas-ZarateC, AuladellC, CaminsA (2013) Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models. Int J Biochem Cell Biol45, 1377–1388.
83.
HalliwellB, GutteridgeJMC (1985) Free Radicals in Biology and Medicine, Clarendon Press.
ButterfieldDA, Boyd-KimballD (2018) Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease. J Alzheimers Dis62, 1345–1367.
86.
Di DomenicoF, TramutolaA, ButterfieldDA (2017) Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. Free Radic Biol Med111, 253–261.
87.
SantosRX, CorreiaSC, ZhuX, LeeHG, PetersenRB, NunomuraA, SmithMA, PerryG, MoreiraPI (2012) Nuclear and mitochondrial DNA oxidation in Alzheimer’s disease. Free Radic Res46, 565–576.
88.
AbolhassaniN, LeonJ, ShengZ, OkaS, HamasakiH, IwakiT, NakabeppuY (2017) Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer’s disease brain. Mech Ageing Dev161, 95–104.
89.
MartinsRN, VillemagneV, SohrabiHR, ChatterjeeP, ShahTM, VerdileG, FraserP, TaddeiK, GuptaVB, Rainey-SmithSR, HoneE, PedriniS, LimWL, MartinsI, FrostS, GuptaS, O’BryantS, RembachA, AmesD, EllisK, FullerSJ, BrownB, GardenerSL, FernandoB, BharadwajP, BurnhamS, LawsSM, BarronAM, GoozeeK, WahjoepramonoEJ, AsihPR, DoeckeJD, SalvadoO, BushAI, RoweCC, GandySE, MastersCL (2018) Alzheimer’s disease: A journey from amyloid peptides and oxidative stress, to biomarker technologies and disease prevention strategies-gains from AIBL and DIAN cohort studies. J Alzheimers Dis62, 965–992.
90.
CastellaniRJ, HarrisPL, SayreLM, FujiiJ, TaniguchiN, VitekMP, FoundsH, AtwoodCS, PerryG, SmithMA (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med31, 175–180.
91.
BenilovaI, KarranE, De StrooperB (2012) The toxic Aβ oligomer and Alzheimer’s disease: An emperor in need of clothes. Nat Neurosci15, 349–357.
CarterJ, LippaCF (2001) Beta-amyloid, neuronal death and Alzheimer’s disease. Curr Mol Med1, 733–737.
94.
McDowellI (2001) Alzheimer’s disease: Insights from epidemiology. Aging (Milano)13, 143–162.
95.
ChandelNS, McClintockDS, FelicianoCE, WoodTM, MelendezJA, RodriguezAM, SchumackerPT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing. J Biol Chem275, 25130–25138.
96.
SunYM, HaoHQ, KongWN, LiuLY, ChaiXQ (2010) [Effect of intracerebroventricular injection of rAAV-HIF-1α on hippocampal neuronal apoptosis in a rat model of Alzheimer disease]. Nan Fang Yi Ke Da Xue Xue Bao30, 2711–2714.
PetersC, BascunanD, BurgosCF, BobadillaC, Gonzalez-SanmiguelJ, BoopathiS, RiffoN, Fernandez-PerezEJ, TarnokME, AguilarLF, GonzalezW, AguayoLG (2020) Characterization of a new molecule capable of inhibiting several steps of the amyloid cascade in Alzheimer’s disease. Neurobiol Dis141, 104938.
99.
KupershmidtL, AmitT, Bar-AmO, YoudimMB, WeinrebO (2012) The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer’s disease. Antioxid Redox Signal17, 860–877.
100.
MechlovichD, AmitT, Bar-AmO, MandelS, YoudimM, WeinrebO (2014) The novel multi-target iron chelator, M30 modulates HIF-1α-related glycolytic genes and insulin signaling pathway in the frontal cortex of APP/PS1 Alzheimer’s disease mice. Curr Alzheimer Res11, 119–127.
101.
FarrAC, XiongMP (2021) Challenges and opportunities of deferoxamine delivery for treatment of Alzheimer’s disease, Parkinson’s disease, and intracerebral hemorrhage. Mol Pharm18, 593–609.
102.
FineJM, RennerDB, ForsbergAC, CameronRA, GalickBT, LeC, ConwayPM, StroebelBM, FreyWH2nd, HansonLR (2015) Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation. Neurosci Lett584, 362–367.
103.
GuoC, WangP, ZhongML, WangT, HuangXS, LiJY, WangZY (2013) Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int62, 165–172.
104.
GuoC, ZhangYX, WangT, ZhongML, YangZH, HaoLJ, ChaiR, ZhangS (2015) Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1alpha pathway on the brain of APP/PS1 transgenic mice. Front Aging Neurosci7, 104.
105.
ZamanK, RyuH, HallD, O’DonovanK, LinKI, MillerMP, MarquisJC, BarabanJM, SemenzaGL, RatanRR (1999) Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J Neurosci19, 9821–9830.
106.
GuoC, YangZH, ZhangS, ChaiR, XueH, ZhangYH, LiJY, WangZY (2017) Intral lactoferrin enhances α-secretase-dependent amyloid precursor protein processing via the ERK1/2-CREB and HIF-1α pathways in an Alzheimer’s disease mouse model. Neuropsychopharmacology42, 2504–2515.
107.
JeongJH, YumKS, ChangJY, KimM, AhnJY, KimS, LapchakPA, HanMK (2015) Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells. BMC Neurol15, 127.
