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Brain Sci. 2018, 8(2), 27; https://doi.org/10.3390/brainsci8020027

ABCA7 and Pathogenic Pathways of Alzheimer’s Disease

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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Author to whom correspondence should be addressed.
Received: 28 December 2017 / Revised: 1 February 2018 / Accepted: 3 February 2018 / Published: 5 February 2018
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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. View Full-Text
Keywords: ABCA1; amyloid-β; amyloid precursor protein; cholesterol; genetics; macrophage; microglia; neurons; phagocytosis; phospholipids ABCA1; amyloid-β; amyloid precursor protein; cholesterol; genetics; macrophage; microglia; neurons; phagocytosis; phospholipids
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Aikawa, T.; Holm, M.-L.; Kanekiyo, T. ABCA7 and Pathogenic Pathways of Alzheimer’s Disease. Brain Sci. 2018, 8, 27.

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