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

Courtney Alexander, Thomas Li, Yorito Hattori, Danica Chiu, Georgia R. Frost, Lauren Jonas, Chenge Liu, Corey J. Anderson, Eitan Wong, Laibaik Park, Costantino Iadecola, Yue Ming Li

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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% 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.

Original languageEnglish
Pages (from-to)4264-4273
Number of pages10
JournalMolecular Psychiatry
Volume27
Issue number10
DOIs
StatePublished - Oct 2022
Externally publishedYes

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