ABCA7 and Pathogenic Pathways of Alzheimer's Disease

Abstract

The ATP-binding cassette (ABC) reporter family functions to regulate the homeostasis of phospholipids and cholesterol in the central nervous system, as well as peripheral tissues. ABCA7 belongs to the A subfamily of ABC transporters, which shares 54% sequence identity with ABCA1. While ABCA7 is expressed in a variety of tissues/organs, including the brain, recent genome-wide association studies (GWAS) have identified ABCA7 gene variants as susceptibility loci for late-onset Alzheimer's disease (AD). More important, subsequent genome sequencing analyses have revealed that premature termination codon mutations in ABCA7 are associated with the increased risk for AD. Alzheimer's disease is a progressive neurodegenerative disease and the most common cause of dementia, where the accumulation and deposition of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain trigger the pathogenic cascade of the disease. In consistence with human genetic studies, increasing evidence has demonstrated that ABCA7 deficiency exacerbates Aβ pathology using in vitro and in vivo models. While ABCA7 has been shown to mediate phagocytic activity in macrophages, ABCA7 is also involved in the microglial Aβ clearance pathway. Furthermore, ABCA7 deficiency results in accelerated Aβ production, likely by facilitating endocytosis and/or processing of APP. Taken together, current evidence suggests that ABCA7 loss-of-function contributes to AD-related phenotypes through multiple pathways. A better understanding of the function of ABCA7 beyond lipid metabolism in both physiological and pathological conditions becomes increasingly important to explore AD pathogenesis.

Keywords: ABCA1; amyloid precursor protein; amyloid-β; cholesterol; genetics; macrophage; microglia; neurons; phagocytosis; phospholipids.

Figure 1

Topological model of ABCA7. The full-length ABCA7 is predicted to possess two hydrophobic transmembrane domains and two large loops serving as substrate-binding domains by OCTOPUS [39]. In addition, ABCA7 has two nucleotide binding domains (NBDs) composed of three motifs: Walker A, Walker B, and the signature motifs [40]. Lipid species are transported across the membrane bilayer through binding of ATP to the NBDs.

Figure 2

Possible pathogenic pathways mediated by ABCA7 in AD. ABCA7 dysregulation may influence the properties of brain cell types, in particular neurons and microglia, by disturbing brain lipid homeostasis and/or through unknown direct mechanisms. Those alterations likely facilitate APP processing and suppress cellular Aβ clearance, contributing to AD development. During the disease progression, ABCA7 deficiency may also exacerbate neuronal damages and diminish microglial phagocytic ability.