ABCG1 influences the brain cholesterol biosynthetic pathway 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 Lütjohann,Ronald B Demattos,Cheryl L Wellington

doi:10.1194/jlr.m700481-jlr200

Abstract

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Abeta production. To clarify the in vivo roles of ABCG1 in Abeta metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Abeta, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Abeta levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Abeta metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.

Highlights

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer’s disease (AD)
Human ABCG1 functionally compensates for loss of endogenous murine ABCG1 and completely prevents lipid accumulation in the lungs of mice challenged with a high-fat, high-cholesterol diet (Burgess et al, under revision), conclusively proving that the human ABCG1 transgene is functional in vivo
Compared with the levels in wild-type cortex, ABCG1 protein levels in ABCG1-bacterial artificial chromosome (BAC)-Tg mice were increased by approximately 6-fold (P, 0.001, N 5 3) in cortex, 8-fold (P, 0.05, N 5 3) in hippocampus, and 6-fold (P, 0.05, N 5 3) in cerebellum (Fig. 1A). These data demonstrate that the ABCG1-BAC is robustly expressed in brain under baseline conditions. Because these ABCG1-BAC-Tg mice would be used to study the effect of excess ABCG1 on Ab metabolism, we further verified that ABCG1 protein levels remained elevated in hippocampus (Fig. 1B) and cortex after crossing to PDAPP mice (ABCG1/PDAPP mice)

Summary

Introduction

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer’s disease (AD). To clarify the in vivo roles of ABCG1 in Ab metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Ab, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Functions for ABCG1 in cholesterol efflux and Ab metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.—Burgess, B. ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. This article is available online at http://www.jlr.org

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