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.

Keywords: Abca1; Alzheimer's disease; Amyloid beta; Cardiovascular disease; HDL; LXR; RXR; apoA-I; apoE.

Figure 1. Mechanism of ABCA1-dependant cholesterol efflux

Step 1: ABCA1 monomer diffuses freely and translocates lipids on the plasma membrane by ATP-dependent mechanism. Step 2: Upon reserving sufficient cholesterol and phospholipids ABCA1 undergoes conformational changes and forms dimers. The lipidated ABCA1 dimers interact with the actin filaments in the plasma membrane and are immobilized until lipid-free apoA-I directly binds to the extracellular domains of ABCA1 dimer. Step 3: ApoA-I or another apolipoprotein accepts the lipids transclocated by ABCA1 leading to the formation of discoidal HDL. After transferring cholesterol and phospholipids to apoA-I, ABCA1-dimer dissociates into monomers and resumes its function to translocate lipids. (according to the model proposed by Nagata et al.)

Figure 2. A simplified model explaining the role of ABCA1 in Aβ deposition and clearance on both sides of the BBB

In the brain ABCA1 mediates apoE lipidation that can affect Aβ metabolism on several levels: (a) decreases Aβ aggregation and prevents its conversion into toxic oligomers or fibrils; (b) enables Aβ clearance by glia or degradation by extracellular proteases; (c) facilitates Aβ removal from the brain through BBB or drainage into CSF. In plasma, ABCA1 is essential for HDL level that could affect Aβ clearance by the mechanism of “peripheral sink” (d).