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Analysis of presenilin/γ-secretase complex responsible for the generation of Aβ in Alzheimer's disease

分析负责阿尔茨海默病中 Aβ 生成的早老素/γ-分泌酶复合物

基本信息

批准号：
13480255
负责人：
IWATSUBO Takeshi
金额：
$ 9.34万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13480255/
关键词：
Alzheimer Presenilin β-amyloid γ-secretase γセレクターゼアルツハイマー病

项目摘要

Deposition of amyloid β peptides (Aβ) as senile plaques (SP) and cerebrovascular amyloid characterizes the neuropathology of Alzheimer's disease (AD). It has been shown that mutations in presenilin (i.e., PSi and PS2) genes linked to familial AD (FAD) increase production and secretion of Aβ42, an initially and predominantly depositing Aβ species in all types of AD. PS are involved in the γ-secretase cleavage of a subset of single-pass membrane proteins including β-amyloid precursor protein and Notch. γ-secretase activity requires the formation of a highly stable, high molecular weight (HMW) protein complex comprised of PS and other co-factor membrane proteins. We showed by RNA interference that Drosophila APH-1 (dAPH-1), an isologue of a Notch pathway component in Caenorabditis elegans, is required for γ-secretase activity to generate Aβ in Drosophila S2 cells. Overexpression of dAPH-1, together with nicastrin (NCT), dramatically increases the stabilization of Drosophila PS (Psn) holoproteins that are incorporated into a HMW protein complex. Inactivation of dPEN-2, another Psn cofactor, abrogates accumulation of Psn fragments, whereas promotes stabilization of Psn holoprotein. Co-expression of dPEN-2 with dAPH-1 and dNCT increases the formation of Psn fragments as well as γ-secretase activity to generate Aβ. These data suggest that: (i)APH-1 stabilizes PS holoprotein in collaboration with NCT, whereas PEN-2 elicits the final maturation of γ-secretase complex, conferring its activity and inducing endoproteolysis of PS and (ii)PS, NCT, APH-1 and PEN-2 represent the set of proteins that comprise the major framework of γ-secretase.

淀粉样蛋白β肽（Aβ）作为老年斑（SP）和脑血管淀粉样蛋白沉积是阿尔茨海默病（AD）神经病理学的特征。研究表明，与家族性AD （FAD）相关的早老素（即PSi和PS2）基因突变增加了Aβ42的产生和分泌，Aβ42是所有AD类型中最初和主要沉积的Aβ物种。PS参与γ-分泌酶对包括β-淀粉样蛋白前体蛋白和Notch在内的一类单代膜蛋白的切割。γ-分泌酶的活性需要形成由PS和其他辅因子膜蛋白组成的高度稳定的高分子量（HMW）蛋白复合物。我们通过RNA干扰发现，果蝇APH-1 （dAPH-1）是秀丽隐杆线虫Notch通路组分的分离物，它是果蝇S2细胞中γ-分泌酶活性产生a β所必需的。过表达dAPH-1和nicastrin （NCT）可以显著增加果蝇PS （Psn）全蛋白的稳定性，这些全蛋白被整合到HMW蛋白复合物中。另一种Psn辅助因子dPEN-2的失活消除了Psn片段的积累，同时促进了Psn全蛋白的稳定。dPEN-2与dAPH-1和dNCT的共表达增加了Psn片段的形成以及γ-分泌酶活性以产生Aβ。这些数据表明：(1)APH-1与NCT协同稳定PS全蛋白，而PEN-2诱导γ-分泌酶复合物的最终成熟，赋予其活性并诱导PS的内蛋白水解；(2)PS、NCT、APH-1和PEN-2代表了构成γ-分泌酶主要框架的一组蛋白质。