Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide

Abstract

The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid beta-peptide (Abeta). Here we provide strong evidence that intracellular cholesterol compartmentation modulates the generation of Abeta. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with Abeta production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generation of Abeta through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Abeta generation, indicating their potential for use in the treatment of Alzheimer's disease.

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease

“…Lack of ACAT1 activity reduces the production of Ab. 5 Therefore, our findings suggest that the A/A genotype of rs1044925 may be associated with reduced ACAT1 activity. In addition, we show that healthy carriers of the protective A/A genotype have low CSF cholesterol levels.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Excess free cholesterol in the cell is converted into cholesteryl esters by the enzyme sterol O‐acyltransferase 1 (ACAT1; also known as acyl CoA:cholesterol acyltransferase 1), followed by accumulation in intracellular lipid droplets or efflux through the plasma membrane into the extracellular environment (Chang, Chang, Ohgami, & Yamauchi, 2006). Increasing levels of cholesteryl esters enhance Aβ release in cultured cells, whereas pharmacological inhibition of ACAT1 (for example, CP‐113, 818 treatment) can lead to the reduction in both Aβ and cholesteryl ester (Bhattacharyya & Kovacs, 2010; Hutter‐Paier et al, 2004; Puglielli et al, 2001). …”

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

“…A similar low-grade demyelination (with or without compensatory activation of myelin programs) could also account for the hypomyelination that accompanies human brain aging (Golomb et al, 1995). Additionally, the increased cholesterol synthesis/transport accompanying myelin synthesis might contribute separately to functional decline, because cholesterol metabolism has recently been implicated in AD (Puglielli et al, 2001;Petanceska et al, 2002). Thus we suggest that a chronic demyelinating process and activation of myelin and cholesterol synthesis may act as triggers for inflammation in the aged brain.…”