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Papers In Press, published online ahead of print February 10, 2007
J. Lipid Res., doi:10.1194/jlr.M600542-JLR200
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University of British Columbia, Vancouver, British Columbia V5S 4H4
Corresponding Author: cheryl{at}cmmt.ubc.ca
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 high-density lipoprotein (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 amyloidprotein A production in transfected HEK cells in a manner that requires functional cholesterol transporter activity. ABCG1-expressing cells also exhibit elevated sAPP and sAPP 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 to age- and sex- matched normal controls. Finally, both A and sAPPlevels are elevated 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.
Revised on February 1, 2007
Accepted on February 10, 2007
The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of
-amyloid precursor protein
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