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Cited by 64Alzheimer's disease research and treatmentsNeurological Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion

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Alexander, Courtney, Li, Thomas, Hattori, Yorito, Chiu, Danica, Frost, Georgia R., Jonas, Lauren, Liu, Chenge, Anderson, Corey J. +4 more·2022·Molecular Psychiatry
DOI 10.1038/s41380-022-01676-7PMC PMC9722522
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Abstract

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% O 2. 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.

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  • Predicted HIF1A activation may provide an additional link to APP/Aβ biology because HIF1A has been shown to increase BACE1 expression and γ-secretase activity under hypoxic conditions.

    “Notably, predicted HIF1A activation may provide an additional link to APP/Aβ biology because HIF1A has been shown to increase BACE1 expression and γ-secretase activity under hypoxic conditions (Alexander et al., 2022; Guglielmotto et al., 2009b).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Alexander et al., 2022

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Cited by

Sorted by citations

Authors
Alexander, C., Li, T., Hattori, Y., Chiu, D., Frost, G. R., Jonas, L., Liu, C., Anderson, C. J., Wong, E., Park, L., Iadecola, C., & Li, Y.-M.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Weill Cornell Medicine (US)
  • Cornell University (US)
Corresponding author
Li, Yue-Ming
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-06-28
Volume
27
Issue
10
Pages
4264-4273
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-022-01676-7
PMC
PMC9722522
OpenAlex
W4283640437
Cited by
64
References
9
Citations by year
2026: 24 · 2025: 10 · 2024: 21 · 2023: 8 · 2022: 1
FWCI
6.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • MEXT | Japan Society for the Promotion of Science (120209939)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (1R01NS100447)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
hypoxia-inducible factor-1α, gamma-secretase, BACE1, amyloid-beta production, hypoxia-ischemia, cerebral hypoperfusion, Alzheimer's disease, protein-protein interaction, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Hypoxia, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Amyloid Precursor Protein Secretases

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