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 ␤ peptide (A␤) in the brain. A␤ is thought to be formed from the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts, and cellular cholesterol depletion decreases A␤ 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 A␤. 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 A␤. Expression of ABCA1 led to both decreased ␤-cleavage product of APP Sw (i.e. C99 peptide) and reduced ␥-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.

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

“…A1− leads to an increase in the ER cholesterol pool and raises the substrate level for CYP46A1 at the ER (13), and leads to an increase in 24SOH biosynthesis in neurons. A similar scenario had previously been suggested by Sun et al (52). The increased 24SOH and/or cholesterol concentration in the ER leads to rapid down-regulation of hAPP protein content, perhaps by accelerating its rate of degradation at the ER, thereby limiting its capacity to produce Aβ.…”

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

“…Initial work focused primarily on the ability of LXRs to decrease amyloidogenic processing of APP (28,59). More recently, Koldamova et al (32) extended these in vitro observations to show that short-term treatment of 11-week-old APP23 mice with T0901317 resulted in a marked decrease in soluble levels of A␤40 and A␤42.…”

“…The discovery that SNPs in genes involved in cholesterol metabolism such as Abca1, Abca2, and Cyp46 are associated with increased risk for AD further strengthens this notion (25)(26)(27). Several groups have examined effects of LXR on APP processing (14,28,29), which is sensitive to cellular sterol levels (23). These studies support a possible role for ATP-binding cassette A1 (ABCA1), a transporter for cholesterol and phospholipids and a direct transcriptional target of LXR, in AD.…”

Cholesterol and Alzheimer's disease: A still poorly understood correlation

“…The astrocytic compartment meets neuronal cholesterol demands by secreting cholesterol-apolipoprotein E (apoE) complexes, a mechanism that may involve the activation of the ATP-binding cassette transporter A1 (ABCA1) (9). Moreover, increased levels of ABCA1 were found to lower Ab production in neuronal cultured cells (10), whereas the deletion of ABCA1 gene in AD mouse models was associated with greater Ab deposits (11,12), supporting the idea that cellular cholesterol efflux might influence Ab production. Conversely, Ab peptides have been recently found to exert an inhibitory effect on both cholesterol synthesis (13) and astrocytic ABCA1 expression (14), therefore suggesting the existence of a regulatory cycle connecting APP processing and cholesterol homeostasis.…”