文章基本信息

标题：Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition
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作者：Ying Jiang ; Kerry A. Mullaney ; Corrinne M. Peterhoff 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：4
页码：1630-1635
DOI：10.1073/pnas.0908953107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：An additional copy of the {beta}-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or {beta}-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 ({beta}CTF), all of which elevate the levels of {beta}CTFs. Expression of a mutant form of APP that cannot undergo {beta}-cleavage had no effect on endosomes. Pharmacological inhibition of APP {gamma}-secretase, which markedly reduced A{beta} production but raised {beta}CTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the {beta}CTF of APP, and exclude A{beta} and the {alpha}CTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.
关键词：Alzheimer’s disease ; amyloid precursor protein ; endocytosis ; endosome