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.

缺氧缺血性损伤与患阿尔茨海默病 (AD) 的风险增加有关。人们对这种关联的基本机制知之甚少。在这里，我们报告了缺氧诱导因子 1α (Hif-1α) 在调节 BACE1 和 γ 分泌酶活性中的独特作用，这两种蛋白酶参与了淀粉样蛋白 -β (Aβ) 的产生。我们已经证明，在脑灌注不足或呼吸 10% O ₂引起的脑缺氧中，Hif-1α 上调 BACE1 和 γ 分泌酶活性，从而促进 Aβ 的产生。 Hif-1α 与 γ-分泌酶结合，从而提高活性 γ-分泌酶复合物的量，而不影响缺氧缺血小鼠大脑中单个亚基的水平。此外，全长 Hif-1α 的表达会增加原代神经元培养物中的 BACE1 和 γ 分泌酶活性，而转录无能的 Hif-1α 变体仅激活 γ 分泌酶。这些发现表明，在缺氧缺血条件下，Hif-1α 转录上调 BACE1，并非转录激活 γ 分泌酶以产生 Aβ。因此，Hif-1α 介导的 Aβ 产生可能是对缺氧缺血性损伤的适应性反应，从而导致 AD 风险增加。因此，防止 Hif-1α 与 γ-分泌酶的相互作用可能是治疗 AD 的一种有前途的治疗策略。