文章基本信息

标题：The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of {beta}-amyloid precursor protein
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作者：Tansley, Gavin H. ; Burgess, Braydon L. ; Bryan, Matt T. 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2007
卷号：48
期号：5
页码：1022-1034
DOI：10.1194/jlr.M600542-JLR200
出版社：American Society for Biochemistry and Molecular Biology
摘要：Although intracellular cholesterol levels are known to influencethe proteolysis of ß-amyloid precursor protein (APP),the effect of specific genes that regulate cholesterol metabolismon APP processing remains poorly understood. The cholesteroltransporter ABCG1 facilitates cholesterol efflux to HDL andis expressed in brain. Notably, the human ABCG1 gene maps tochromosome 21q22.3, and individuals with Down syndrome (DS)typically manifest with Alzheimer's disease (AD) neuropathologyin their 30s. Here, we demonstrate that expression of ABCG1enhances amyloid-ß protein (Aß) productionin transfected HEK cells in a manner that requires functionalcholesterol transporter activity. ABCG1-expressing cells alsoexhibit increased secreted APP (sAPP) ${alpha}$ and sAPPß secretionand display increased cell surface-associated APP. These resultssuggest that ABCG1 increases the availability of APP as a secretasesubstrate for both the amyloidogenic and nonamyloidogenic pathways.In vivo, ABCG1 mRNA levels are 2-fold more abundant in DS braincompared with age- and sex-matched normal controls. Finally,both Aß and sAPP ${alpha}$ levels are increased in DS cortexrelative to normal controls. These findings suggest that alteredcholesterol metabolism and APP trafficking mediated by ABCG1may contribute to the accelerated onset of AD neuropathologyin DS. Supplementary key words ATP binding cassette transporter G1 • Alzheimer's disease • amyloid ß proteins • Down syndrome Abbreviations: Aß, amyloid-ß protein; AD, Alzheimer's disease; apoA-I, apolipoprotein A-I; APP, ß-amyloid precursor protein; CTF, C-terminal fragment; DS, Down syndrome; sAPP, secreted APP