The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of beta-amyloid precursor protein |
| |
Authors: | Tansley Gavin H Burgess Braydon L Bryan Matt T Su Yuan Hirsch-Reinshagen Veronica Pearce Jonathan Chan Jeniffer Y Wilkinson Anna Evans Jeanette Naus Kathryn E McIsaac Sean Bromley Kelley Song Weihong Yang Hsui-Chiung Wang Nan DeMattos Ronald B Wellington Cheryl L |
| |
Affiliation: | Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. |
| |
Abstract: | Although intracellular cholesterol levels are known to influence the proteolysis of beta-amyloid precursor protein (APP), the effect of specific genes that regulate cholesterol metabolism on APP processing remains poorly understood. The cholesterol transporter ABCG1 facilitates cholesterol efflux to HDL and is expressed in brain. Notably, the human ABCG1 gene maps to chromosome 21q22.3, and individuals with Down syndrome (DS) typically manifest with Alzheimer's disease (AD) neuropathology in their 30s. Here, we demonstrate that expression of ABCG1 enhances amyloid-beta protein (Abeta) production in transfected HEK cells in a manner that requires functional cholesterol transporter activity. ABCG1-expressing cells also exhibit increased secreted APP (sAPP)alpha and sAPPbeta secretion and display increased cell surface-associated APP. These results suggest that ABCG1 increases the availability of APP as a secretase substrate for both the amyloidogenic and nonamyloidogenic pathways. In vivo, ABCG1 mRNA levels are 2-fold more abundant in DS brain compared with age- and sex-matched normal controls. Finally, both Abeta and sAPPalpha levels are increased in DS cortex relative to normal controls. These findings suggest that altered cholesterol metabolism and APP trafficking mediated by ABCG1 may contribute to the accelerated onset of AD neuropathology in DS. |
| |
Keywords: | ATP binding cassette transporter G1 Alzheimer's disease amyloid β proteins Down syndrome |
本文献已被 ScienceDirect PubMed 等数据库收录! |