Hypoxia Inducible Factor-1 alpha binds and activates gamma-secretase for A beta production under hypoxia and cerebral hypoperfusion

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-1 alpha (Hif-1 alpha) in the regulation of BACE1 and gamma-secretase activity, two proteases involved in the production of amyloid-beta (A beta). We have demonstrated that Hif-1 alpha upregulates both BACE1 and gamma-secretase activity for A beta production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O-2. Hif-1 alpha 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-1 alpha increases BACE1 and gamma-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1 alpha variant only activates gamma-secretase. These findings indicate that Hif-1 alpha transcriptionally upregulates BACE1 and nontranscriptionally activates gamma-secretase for A beta production in hypoxic-ischemic conditions. Consequently, Hif-1 alpha-mediated A beta production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1 alpha with gamma-secretase may therefore be a promising therapeutic strategy for AD treatment.