ABCG1 influences brain cholesterol synthesis but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Braydon L. Burgess, Pamela F. Parkinson, Margaret M. Racke, Veronica Hirsch-Reinshagen, Jianjia Fan, Charmaine Wong, Sophie Stukas, Louise Theroux, Jeniffer Y. Chan, James Donkin, Anna Wilkinson, Danielle Balik, Brian Christie, Judes Poirier, Dieter Lutjohann, Ronald B. DeMattos, and Cheryl L. Wellington

University of British Columbia, Vancouver, British Columbia V6z 4H4

Corresponding Author: cheryl{at}cmmt.ubc.ca

Cholesterol biosynthesis has a complex relationship with the pathogenesis of Alzheimer’s Disease (AD), and genes that regulate cholesterol homeostasis are of potential therapeutic importance for this devastating disease. Genes that respond to LXR agonists are of particular interest, as synthetic liver-X-receptor (LXR) agonists decrease neuropathological and cognitive phenotypes in AD mouse models, whereas LXRa/ß deficient mice exhibit increased Aß and amyloid deposition. The cholesterol transporter ABCG1 is highly expressed in brain and responds to LXR stimulation. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Aß production and secretion from APP-expressing cells. To clarify the in vivo roles of selective ABCG1 overexpression in Aß metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess ABCG1. We observed that a 6-fold increase in ABCG1 levels did not alter Aß, amyloid, apoE levels, or cholesterol efflux, nor did it alter cognitive performance. Furthermore, endogenous murine Aß levels were not robustly changed in either ABCG1-overexpressing or in ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, ABCG1 does affect brain sterol homeostasis in vivo. Excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMGCoA-R mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Aß metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter is largely one of regulating the sterol biosynthetic pathway.

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