|Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion.
|Year of Publication
|Alexander C, Li T, Hattori Y, Chiu D, Frost GR, Jonas L, Liu C, Anderson CJ, Wong E, Park L, Iadecola C, Li Y-M
|2022 Jun 28
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.
|120209939 / / MEXT | Japan Society for the Promotion of Science (JSPS) /
1R01NS100447 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /