Expression of liver X receptor target genes decreases cellular amyloid β peptide secretion

Abstract

A hallmark of Alzheimer's disease is the deposition of plaques of amyloid β peptide (Aβ) in the brain. Aβ is thought to be formed from the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts, and cellular cholesterol depletion decreases Aβ formation. The liver X receptors (LXR) play a key role in regulating genes that control cellular cholesterol efflux and membrane composition and are widely expressed in cells of the central nervous system. We show that treatment of APP-expressing cells with LXR activators reduces the formation of Aβ. LXR activation resulted in increased levels of the ATP-binding cassette transporter A1 (ABCA1) and stearoyl CoA desaturase, and expression of these genes individually decreased formation of Aβ. Expression of ABCA1 led to both decreased β-cleavage product of APPSw (i.e. C99 peptide) and reduced γ-secretase-cleavage of C99 peptide. Remarkably, these effects of ABCA1 on APP processing were independent of cellular lipid efflux. LXR and ABCA1-induced changes in membrane lipid organization had favorable effects on processing of APP, suggesting a new approach to the treatment of Alzheimer's disease.