Hypoxia inducible factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion Journal Article
| 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. |
| Article Title: | Hypoxia inducible factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion |
| 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-1alpha (Hif-1alpha) in the regulation of BACE1 and gamma-secretase activity, two proteases involved in the production of amyloid-beta (Abeta). We have demonstrated that Hif-1alpha upregulates both BACE1 and gamma-secretase activity for Abeta production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O2. Hif-1alpha binds to gamma-secretase, which elevates the amount of active gamma-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1alpha increases BACE1 and gamma-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1alpha variant only activates gamma-secretase. These findings indicate that Hif-1alpha transcriptionally upregulates BACE1 and nontranscriptionally activates gamma-secretase for Abeta production in hypoxic-ischemic conditions. Consequently, Hif-1alpha-mediated Abeta production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1alpha with gamma-secretase may therefore be a promising therapeutic strategy for AD treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved) |
| Journal Title: | Molecular Psychiatry |
| Volume: | 27 |
| Issue: | 10 |
| ISSN: | 1359-4184 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-10-01 |
| Start Page: | 4264 |
| End Page: | 4273 |
| ACCESSION: | 2022-78117-001 |
| DOI: | 10.1038/s41380-022-01676-7 |
| PROVIDER: | Ovid Technologies |
| PROVIDER: | psycinfo |
| PUBMED: | 35764706 |
| PMCID: | PMC9722522 |
| DOI/URL: | |
| Notes: | Source: APA PsycInfo |
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