Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels

Abstract

The expression, function, and regulation of the cholesterol efflux molecule, ABCA1, has been extensively examined in peripheral tissues but only poorly studied in the brain. Brain cholesterol metabolism is of interest because several lines of evidence suggest that elevated cholesterol increases the risk of Alzheimer's disease. We found a largely neuronal expression of ABCA1 in normal rat brain by in situ hybridization. ABCA1 message was dramatically up-regulated in neurons and glia in areas of damage by hippocampal AMPA lesion after 3-7 days. Immunoblot analysis demonstrated ABCA1 protein in cultured neuronal and glial cells, and expression was induced by ligands of the nuclear hormone receptors of the retinoid X receptor and liver X receptor family. ABCA1 was induced by treatment with retinoic acid and several oxysterols, including 22(R)-hydroxycholesterol and 24-hydroxycholesterol. Expression of an ABCA1-green fluorescent protein construct in neuroblastoma cells demonstrated fluorescence in perinuclear compartments and on the plasma membrane. Because the A␤ peptide is important in Alzheimer's disease pathogenesis, we examined whether ABCA1 induction altered A␤ levels. Treatment of neuroblastoma cells with retinoic acid and 22(R)-hydroxycholesterol caused significant increases in secreted A␤40 (29%) and A␤42 (65%). Treatment with a nonsteroidal liver X receptor ligand, TO-901317, similarly increased levels of secreted A␤40 (25%) and A␤42 (126%). The increase in secreted A␤ levels was reduced by RNAi blocking of ABCA1 expression. These data suggest that the cholesterol efflux molecule ABCA1 may also be involved in the secretion of the membrane-associated molecule, A␤.ABCA1 encodes an ATP-binding cassette protein that promotes efflux of cholesterol and phospholipids from intracellular compartments to high density lipoprotein, lipid-deficient apoAI, 1 and other apolipoproteins (1). Disruption of ABCA1 byTangier disease mutations in humans or by engineered knockout in mice is associated with a loss of cellular cholesterol efflux, an ablation of circulating high density lipoprotein, and, interestingly, peripheral neuropathies (2-5). Like many genes involved in cholesterol homeostasis, ABCA1 is regulated by the liver X receptors (LXR) (6 -8), nuclear receptors activated by oxysterols. ABCA1 is also regulated by peroxisome proliferatoractivated receptor ␦, which can be activated by fatty acid metabolites (9). Both of these classes of receptors form heterodimers with retinoid X receptors (RXR), which bind retinoic acid; as heterodimers, they alter gene transcription. These systems for ABCA1 induction help decrease cellular cholesterol after cholesterol loading (10). The importance of cerebral cholesterol metabolism in Alzheimer's disease (AD) risk and pathogenesis is supported by genetic, cell culture, mouse model, and epidemiologic data. ApoE in the central nervous system is implicated in supplying appropriate membrane lipid for development, nerve growth, and responses to injury and repair in the central nervous syste...

Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

“…That ABCA1 can directly influence Ab has been demonstrated (Fukumoto et al 2002), and more recent evidence suggests that ABCA1 also interacts with APOE in the CNS (Hirsch-Reinshagen et al 2004). In the present study, we suggest that genetic variants of ABCA1 may influence CSF Ab 1-42 levels, possibly reflecting its involvement with Ab metabolism.…”

“…Recent studies have shown that deficiency of ABCA1 in the brain leads to a specific decrease in APOE levels (Hirsch-Reinshagen et al 2004;Wahrle et al 2004). Interestingly, ABCA1 shares a commonality with APOE in that it appears to be involved in Ab metabolism (Fukumoto et al 2002); this is supported by evidence suggesting a relationship between cholesterol metabolism and Ab metabolism (Simons et al 1998(Simons et al , 2001Kojro et al 2001). Emerging data thus suggest that ABCA1 plays an important role in lipid metabolism in both peripheral tissues and the central nervous system (CNS) and, like APOE, may also influence Ab.…”

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…With its expression in liver and brain, ABCB1 -the prototype of the B subclass of transporters -and ABCA1 regulate the high-density lipoprotein levels in the plasma and cholesterol contents of several cell types in these organs [106][107][108][109][110][111][112][113][114]. Most interestingly, the ABCB1 transporter also shows strong expression in neurons of the hippocampus formation, particularly in the granule cells of the DG [85].…”

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

“…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.…”