ATP-binding cassette transporter A1: From metabolism to neurodegeneration

Abstract

ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of High Density Lipoproteins (HDL) and reverse cholesterol transport – a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer’s disease (AD). A series of reports have revealed a significant impact of ABCA1 on Aβ deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.

Relation between plasma and brain lipids

“…ApoA-I is abundant in the CSF of many species, yet the physiological roles of both circulating and CSF apoA-I on brain functions are not well understood [24,25,64]. Emerging data suggest that serum apoA-I levels may influence cognitive function independent of APOE genotype and amyloid burden.…”

“…Both ABCA1 and apoE are transcriptionally induced through the liver X receptor (LXR) and retinoid X receptor (RXR) pathways, and a large body of evidence shows that the lipidation status of apoE is a critical determinant of many of its functions including amyloid-b metabolism, inflammation, and cognition [64,74,75]. For example, both genetic manipulation of ABCA1 or LXR levels as well as pharmacologic manipulation of ABCA1 activity using LXR or RXR agonists show that increased lipidated apoE improves cognitive performance and can lower amyloid-b burden in Alzheimer's disease mouse models, whereas decreasing apoE lipidation by ABCA1 deficiency exacerbates Alzheimer's disease pathology [76][77][78][79][80][81].…”

ABCA1 and Inflammation

“…13 The ability of ABCA1 to mobilize cellular cholesterol and efflux it to acceptor particles, as well as its direct involvement in signaling pathways 14 may contribute to these effects. Translating findings from in vitro and inbred animal models into humans is not straightforward, as demonstrated by conflicting results in the role of ABCA1 in insulin secretion, 15,16 Alzheimer disease 17 and even in cardiovascular risk. 18,19 Macrophage-specific ABCA1 deficiency is associated with increased proinflammatory gene expression and cytokine release both in vivo in animal models and in vitro ( Figure).…”

LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice

“…Lipidation of apoE in the CNS is performed by ABCA1 ( 28,29 ), akin to the well-established role of ABCA1-mediated lipidation of apoA-I in the periphery ( 30 ). Plasma and CSF apoA-I levels are markedly reduced in mice defi cient in ABCA1, whereas CSF and brain tissue apoE are decreased by 60-80% ( 28,29,31 ).…”