Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimer’s disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aβ). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aβ production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O2. Hif-1α binds to γ-secretase, which elevates the amount of active γ-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1α increases BACE1 and γ-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1α variant only activates γ-secretase. These findings indicate that Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase for Aβ production in hypoxic-ischemic conditions. Consequently, Hif-1α-mediated Aβ production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1α with γ-secretase may therefore be a promising therapeutic strategy for AD treatment.
Your institute does not have access to this article
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004;5:347–60.
Santos CY, Snyder PJ, Wu WC, Zhang M, Echeverria A, Alber J. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis. Alzheimers Dement. 2017;7:69–87.
Knopman DS, Amieva H, Petersen RC, Chetelat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Prim. 2021;7:33.
Cortes-Canteli M, Iadecola C. Alzheimer’s disease and vascular aging: JACC Focus Seminar. J Am Coll Cardiol. 2020;75:942–51.
Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, et al. Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA. 2006;103:18727–32.
Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, et al. Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem. 2007;282:10873–80.
De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003;38:9–12.
Wang R, Zhang YW, Zhang X, Liu R, Hong S, Xia K, et al. Transcriptional regulation of APH-1A and increased gamma-secretase cleavage of APP and Notch by HIF-1 and hypoxia. FASEB J. 2006;20:1275–7.
Li L, Zhang X, Yang D, Luo G, Chen S, Le W. Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging. 2009;30:1091–8.
Villa JC, Chiu D, Brandes AH, Escorcia FE, Villa CH, Maguire WF, et al. Nontranscriptional role of Hif-1α in activation of γ-secretase and notch signaling in breast cancer. Cell Rep. 2014;8:1077–92.
Gertsik N, Chiu D, Li YM. Complex regulation of gamma-secretase: from obligatory to modulatory subunits. Front Aging Neurosci. 2014;6:342.
Wong E, Frost GR, Li YM. γ-Secretase modulatory proteins: the guiding hand behind the running scissors. Front Aging Neurosci. 2020;12:614690.
Hur JY, Frost GR, Wu X, Crump C, Pan SJ, Wong E, et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature. 2020;586:735–40.
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature. 2010;467:95–98.
Wong E, Liao GP, Chang JC, Xu P, Li YM, Greengard P. GSAP modulates γ-secretase specificity by inducing conformational change in PS1. Proc Natl Acad Sci USA. 2019;116:6385–90.
Jung S, Hyun J, Nah J, Han J, Kim SH, Park J, et al. SERP1 is an assembly regulator of gamma-secretase in metabolic stress conditions. Sci Signal. 2020; 13:eaax8949
Ding B, Kilpatrick DL. Lentiviral vector production, titration, and transduction of primary neurons. Methods Mol Biol. 2013;1018:119–31.
Chun J, Yin YI, Yang G, Tarassishin L, Li YM. Stereoselective synthesis of photoreactive peptidomimetic gamma-secretase inhibitors. J Org Chem. 2004;69:7344–7.
Placanica L, Tarassishin L, Yang G, Peethumnongsin E, Kim SH, Zheng H, et al. Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes. J Biol Chem. 2009;284:2967–77.
Placanica L, Chien JW, Li YM. Characterization of an atypical gamma-secretase complex from hematopoietic origin. Biochemistry. 2010;49:2796–804.
Placanica L, Zhu L, Li YM. Gender- and age-dependent gamma-secretase activity in mouse brain and its implication in sporadic Alzheimer disease. PLoS One. 2009;4:e5088.
Coleman CG, Wang G, Park L, Anrather J, Delagrammatikas GJ, Chan J, et al. Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. J Neurosci. 2010;30:12103–12.
Hattori Y, Kitamura A, Nagatsuka K, Ihara M. A novel mouse model of ischemic carotid artery disease. PLOS ONE. 2014;9:e100257.
Koizumi K, Hattori Y, Ahn SJ, Buendia I, Ciacciarelli A, Uekawa K, et al. Apoepsilon4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat Commun. 2018;9:3816.
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689–94.
Chau DM, Crump CJ, Villa JC, Scheinberg DA, Li YM. Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of gamma-secretase. J Biol Chem. 2012;287:17288–96.
Tian Y, Bassit B, Chau D, Li YM. An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production. Nat Struct Mol Biol. 2010;17:151–8.
Li YM, Lai MT, Xu M, Huang Q, DiMuzio-Mower J, Sardana MK, et al. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc Natl Acad Sci USA. 2000;97:6138–43.
Koizumi K, Hattori Y, Ahn SJ, Buendia I, Ciacciarelli A, Uekawa K, et al. Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function. Nat Commun. 2018;9:3816.
Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Abeta production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation. 2011;8:150.
Frost GR, Li YM. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol. 2017;7:170228.
Crump CJ, AM Ende CW, Ballard TE, Pozdnyakov N, Pettersson M, Chau DM, et al. Development of clickable active site-directed photoaffinity probes for gamma-secretase. Bioorg Med Chem Lett. 2012;22:2997–3000.
Nie P, Vartak A, Li YM. gamma-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of gamma-Secretase. Semin Cell Dev Biol. 2020;105:43–53.
Washida K, Hattori Y, Ihara M. Animal models of chronic cerebral hypoperfusion: from mouse to primate. Int J Mol Sci. 2019;20:6176.
Güner G, Lichtenthaler SF. The substrate repertoire of γ-secretase/presenilin. Semin Cell Dev Biol. 2020;105:27–42.
Lai MT, Chen E, Crouthamel MC, DiMuzio-Mower J, Xu M, Huang Q, et al. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. J Biol Chem. 2003;278:22475–81.
Liu L, Lauro BM, Ding L, Rovere M, Wolfe MS, Selkoe DJ. Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life. Alzheimers Dement. 2019;15:1183–94.
Capell A, Steiner H, Willem M, Kaiser H, Meyer C, Walter J, et al. Maturation and pro-peptide cleavage of beta-secretase. J Biol Chem. 2000;275:30849–54.
Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422:438–41.
Herreman A, Van Gassen G, Bentahir M, Nyabi O, Craessaerts K, Mueller U, et al. gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. J Cell Sci. 2003;116:1127–36. Pt 6
Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem. 1997;272:24536–41.
Berra E, Roux D, Richard DE, Pouyssegur J. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) escapes O(2)-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm. EMBO Rep. 2001;2:615–20.
Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002;22:7405–16.
Wollenick K, Hu J, Kristiansen G, Schraml P, Rehrauer H, Berchner-Pfannschmidt U, et al. Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling. Nucleic Acids Res. 2012;40:1928–43.
O’Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, et al. Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron. 2008;60:988–1009.
Suh J, Romano DM, Nitschke L, Herrick SP, DiMarzio BA, Dzhala V, et al. Loss of Ataxin-1 potentiates Alzheimer’s pathogenesis by elevating Cerebral BACE1 transcription. Cell. 2019;178:1159–1175 e1117.
Brothers HM, Gosztyla ML, Robinson SR. The Physiological roles of amyloid-beta peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci. 2018;10:118.
Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, et al. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science. 2008;321:1221–4.
Lee PH, Bang OY, Hwang EM, Lee JS, Joo US, Mook-Jung I, et al. Circulating beta amyloid protein is elevated in patients with acute ischemic stroke. J Neural Transm. 2005;112:1371–9.
Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, et al. Tau elevations in the brain extracellular space correlate with reduced amyloid-beta levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain. 2012;135:1268–80. Pt 4
Koike MA, Lin AJ, Pham J, Nguyen E, Yeh JJ, Rahimian R, et al. APP knockout mice experience acute mortality as the result of ischemia. PLoS One. 2012;7:e42665.
Clarke J, Thornell A, Corbett D, Soininen H, Hiltunen M, Jolkkonen J. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur J Neurosci. 2007;26:1845–52.
Mannix RC, Zhang J, Berglass J, Qui J, Whalen MJ. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 2013;27:743–8.
Vangeison G, Carr D, Federoff HJ, Rempe DA. The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes. J Neurosci. 2008;28:1988–93.
Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 2010;120:287–96.
Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844–66.
Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67:181–98.
Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Perez JM, Evans AC. Alzheimer’s disease Neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun. 2016;7:11934.
Zetterberg H, Mortberg E, Song L, Chang L, Provuncher GK, Patel PP, et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid beta levels in humans. PLoS One. 2011;6:e28263.
Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol. 1988;23:138–44.
Crystal H, Dickson D, Fuld P, Masur D, Scott R, Mehler M, et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer’s disease. Neurology. 1988;38:1682–7.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80.
Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021;372:n156.
Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, et al. Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. 2021;7:eabb5398.
Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, et al. Transformative network modeling of multi-omics data reveals detailed circuits, key regulators, and potential therapeutics for Alzheimer’s disease. Neuron. 2021;109:257–272 e214.
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153:707–20.
This work is supported by the National Institutes of Health R01AG061350(YML), R01NS096275 (YML), RF1AG057593 (YML), 1R01NS100447 (CI), R01NS/HL37853 (CI) and the JPB Foundation (YML), Bilateral Research Joint Projects of Japan Society for the Promotion of Science, 120209939 (YH). Authors also acknowledge the MSK Cancer Center Support Grant/Core Grant (Grant P30 CA008748), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, and the William Randolph Hearst Fund in Experimental Therapeutics.
Conflict of interest
LYM is a co-inventor of intellectual property (assay for gamma secretase activity and screening method for gamma secretase inhibitors) owned by MSKCC and licensed to Jiangsu Continental Medical Development. CI serves on the Scientific Advisory Board of Broadview Ventures.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Alexander, C., Li, T., Hattori, Y. et al. Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01676-7