缺氧(环境)
淀粉样前体蛋白分泌酶
下调和上调
蛋白酵素
缺氧诱导因子
神经科学
细胞生物学
生物
化学
药理学
癌症研究
医学
淀粉样前体蛋白
阿尔茨海默病
内科学
疾病
生物化学
酶
基因
有机化学
氧气
作者
Courtney Alexander,Thomas Li,Yorito Hattori,Danica Chiu,Georgia Frost,Lauren A. Jonas,Chenge Liu,Corey Anderson,Eitan Wong,Laibaik Park,Costantino Iadecola,Yue-Ming Li
标识
DOI:10.1038/s41380-022-01676-7
摘要
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.
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