Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis
Presenilin is essential for ApoE secretion, a novel role of presenilin involved in Alzheimer's disease pathogenesis
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DOI：
10.1523/jneurosci.2039-21.2021
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发表时间：
2022-02-23
影响因子：
5.3
通讯作者：
Michikawa, Makoto
中科院分区：
文献类型：
--
作者：
Islam, Sadequl;Sun, Yang;Michikawa, Makoto
阿尔茨海默病（Alzheimer disease，AD）是一种以进行性记忆丧失和淀粉样β蛋白（A β）聚集成患者大脑中的淀粉样斑块为特征的衰弱性痴呆。早老素（PS）基因突变导致A β生成异常，是家族性AD（FAD）的主要病因，载脂蛋白E4（ApoE 4）是散发性AD（SAD）发病的主要遗传危险因素。然而，PS功能障碍是否参与SAD的发病机制在很大程度上是未知的。我们发现，载脂蛋白E分泌完全废除PS缺陷细胞和γ-分泌酶活性的抑制显着下降。γ-分泌酶抑制剂DAPT阻断γ-分泌酶活性可降低ApoE分泌，表明γ-分泌酶活性在ApoE分泌中发挥重要作用。在γ-分泌酶活性降低的nicastrin（NCT）缺陷细胞中也观察到ApoE分泌减少。PS缺陷增强了ApoE的核转位和ApoE与核转运受体importin α 4的结合。此外，PS突变体在PS缺陷细胞中的表达抑制了对ApoE分泌的恢复作用。与正常对照组相比，携带PS1突变的FAD患者血浆ApoE水平较低。我们的研究结果表明PS通过调节ApoE分泌在SAD发病中发挥新的作用。显著性StatementFAD通常由编码淀粉样前体蛋白（APP）的基因PS1或PS2突变引起。已发现许多PS突变体产生γ-分泌酶活性受损和A β 42/A β 40比值增加，从而诱导早期淀粉样蛋白沉积和FAD。另一方面，ApoE 4是SAD的主要遗传风险因素，并有助于AD发病机制，因为与ApoE 3和ApoE 2相比，ApoE 4具有降低的A β清除能力。FAD和SAD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是ApoE分泌所必需的，并且PS突变体在体外和人体样品中影响ApoE分泌，这表明PS也参与SAD发病的新机制。
Alzheimer disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-p-protein (A beta) into amyloid plaques in patient brain. Mutations in presenilin (PS) lead to abnormal generation of A beta, 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 gamma-secretase activity. Blockade of gamma-secretase activity by a gamma-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of gamma-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin (NCT) deficient cells with reduced gamma-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin alpha 4, a nuclear-transport receptor. Moreover, expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal controls. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.Significance StatementFAD typically results from mutations in the genes encoding amyloid precursor protein (APP), PS1 or PS2. Many PS mutants have been found to exert impaired y-secretase activity and increased A beta 42/A beta 40 ratio, which induce early amyloid deposition and FAD. On the other hand, ApoE4 is the major genetic risk factor for SAD and contributes to AD pathogenesis because it has reduced A beta 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 in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.