Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd., B13, Pudongxinqu, Shanghai 201210, China.
Neuron. 2023 Jun 21;111(12):1898-1913.e5. doi: 10.1016/j.neuron.2023.03.024. Epub 2023 Apr 10.
Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.
异常低的γ-分泌酶活性与大多数导致家族性阿尔茨海默病（fAD）的早老素突变有关。然而，γ-分泌酶在更为普遍的散发性 AD（sAD）中的作用仍未得到解决。在这里，我们报告人类载脂蛋白 E（ApoE），sAD 的最重要遗传风险因素，通过其保守的 C 端区域（CT）与 γ-分泌酶相互作用，并以细胞自主的方式具有底物特异性抑制它。这种 ApoE CT 介导的抑制活性在不同的 ApoE 异构体中受到不同程度的损害，导致 ApoE2 > ApoE3 > ApoE4 的效力等级与它们相关的 AD 风险呈负相关。有趣的是，在 AD 小鼠模型中，神经元 ApoE CT 从其他区域迁移到海马下的淀粉样斑块，减轻斑块负担。总之，我们的数据揭示了 ApoE 作为一种具有底物特异性的 γ-分泌酶抑制剂的隐藏作用，并表明这种由 ApoE 介导的精确 γ-抑制可能有助于预防 sAD 的风险。
