ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Abstract

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1−) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1− causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1− causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1− causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.Alzheimer disease | cholesterol esterification | lipid metabolism | oxysterols

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

“…Bryleva et al (37) measured the CE content in mouse brains by separating the CE fraction from the free cholesterol fraction using silica column chromatography. They then determined the cholesterol content present in CE by GC/MS after CE was saponified.…”

“…Hudry et al did not observe a reduction in the hAPP protein content; instead, they demonstrated a decrease in hAPP processing by gamma-secretase, an increase in SREBP2 mRNA, and no change in brain cholesterol content. Bryleva et al (37) showed that A12 in 3XTg-AD mice caused a 32% increase in 24SOH content, a modest reduction in cholesterol biosynthesis rate and in brain cholesterol content, and a significant reduction in amyloid pathology. This work implies that a modest increase in 24SOH content can lead to a decrease in the full-length hAPP content.…”

“…Bryleva et al (37) have undertaken a mouse genetic approach, using the Acat12/2, Acat22/2 mice (19), and the triple transgenic (3XTg)-AD mice (75) to investigate the roles of ACAT in a mouse model of AD. This work demonstrated the following: 1) ACAT1 deficiency (A12) in the 3XTg-AD mouse leads to more than 60% reductions in full-length hAPPswe (human APP with the Swedish mutation), as well as its cleavage fragments, and ameliorates cognitive deficits.…”

“…Although the roles of ACAT1 and ACAT2 have been extensively studied in systemic tissues, their expression levels and roles in the central nervous system under normal and pathophysiological conditions are much less clear. Recently, Bryleva et al (37) demonstrated that ACAT1 is the major isoenzyme and is functional in vivo in mouse brains. The ACAT2 protein and mRNA levels were nearly undetectable (18,37).…”

“…Recently, Bryleva et al (37) demonstrated that ACAT1 is the major isoenzyme and is functional in vivo in mouse brains. The ACAT2 protein and mRNA levels were nearly undetectable (18,37).…”