Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
J Neurosci. 2022 Feb 23;42(8):1574-1586. doi: 10.1523/JNEUROSCI.2039-21.2021. Epub 2022 Jan 5.
Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion. Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.
阿尔茨海默病（AD）是一种使人虚弱的痴呆症，其特征是进行性记忆丧失以及淀粉样β（Aβ）蛋白在患者大脑中聚集形成淀粉样斑块。早老素（PS）的突变导致 Aβ的异常生成，这是家族性 AD（FAD）的主要原因，载脂蛋白 E4（ApoE4）是散发性 AD（SAD）发病的主要遗传风险因素。然而，PS 的功能障碍是否参与 SAD 的发病机制在很大程度上尚不清楚。我们发现 PS 缺陷细胞中 ApoE 的分泌完全被阻断，并且 γ-分泌酶活性的抑制显著降低了 ApoE 的分泌。γ-分泌酶抑制剂 DAPT 阻断 γ-分泌酶活性，降低了 ApoE 的分泌，表明 γ-分泌酶活性在 ApoE 分泌中起重要作用。γ-分泌酶活性降低的尼卡斯特林缺陷细胞中也观察到 ApoE 分泌减少。PS 缺陷增强了 ApoE 的核易位和与核转运受体 importinα4 的结合。此外，与野生型 PS 的表达相比，PS 缺陷细胞中 PS 突变体的表达抑制了对 ApoE 分泌的恢复作用。与正常对照相比，携带 PS1 突变的 FAD 患者的血浆 ApoE 水平较低。我们的研究结果表明，PS 通过调节 ApoE 分泌，在 SAD 的发病机制中发挥了新的作用。家族性 AD（FAD）通常是由编码淀粉样前体蛋白、早老素 1（PS1）或 PS2 的基因突变引起的。已经发现许多 PS 突变体具有受损的 γ-分泌酶活性和增加的淀粉样β 42（Aβ42）/Aβ40 比值，这导致早期淀粉样沉积和 FAD。另一方面，载脂蛋白 E4（ApoE4）是散发性 AD（SAD）的主要遗传风险因素，并且由于与 ApoE3 和 ApoE2 相比，它具有降低的 Aβ清除能力，从而促进 AD 的发病机制。FAD 和 SAD 长期以来一直被认为是由这两种独立的机制引起的；然而，我们首次证明 PS 对 ApoE 分泌是必不可少的，PS 突变体影响 ApoE 分泌，并且在人类样本中，这表明 PS 也参与 SAD 发病机制的一种新机制。
