ATP-binding Cassette Transporter A7 (ABCA7) Loss of Function Alters Alzheimer Amyloid Processing

Abstract

Background:The ATP-binding cassette transporter A7 (ABCA7) is a risk factor for sporadic Alzheimer disease (AD). Results: Loss of ABCA7 promoted A␤ processing and pathology in cell culture and AD mouse models. Conclusion: Altered ABCA7 function may contribute to AD by impacting A␤ production in addition to clearance. Significance: AD-related risk factors may contribute to disease progression through multiple pathways.The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-␤ (A␤). Suppression of endogenous ABCA7 in several different cell lines resulted in increased ␤-secretase cleavage and elevated A␤. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid A␤42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble A␤ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble A␤ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas A␤ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased A␤ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility.Genome-wide association studies have identified the ATPbinding cassette transporter A7 (ABCA7) 2 as a susceptibility locus for late onset Alzheimer disease (LOAD) (1, 2). The single nucleotide polymorphisms (SNPs) associated with LOAD are distributed in various domains of the ABCA7 gene and include intronic SNPs and a coding sequence causing G1527A substitution. Studies have identified loci in different clusters, suggesting multiple sites within the ABCA7 gene associated with increased risk for AD (3). However, there is no indication that individuals with at-risk alleles display any differences in ABCA7 expression.ABCA7 is a member of the ATP-binding cassette transporter family largely involved in lipid transport and homeostasis (4). Its highly homologous member ABCA1 has also been linked to LOAD through cholesterol and processing of the amyloid precursor protein (5-7). Overexpression of ABCA7 resulted in a significant decrease in amyloid-...

Abca7 deletion does not affect adult neurogenesis in the mouse

“…Studies in cell lines and mouse models suggest that a loss of ABCA7 function may have deleterious consequences for Aβ homoeostasis in the brain [12][13][14]. This is consistent with the previously reported significant association of ABCA7 SNPs with amyloid plaque load in human subjects [6].…”

“…In vitro studies revealed that ABCA7 transfection into cell lines constitutively expressing human amyloid-β precursor protein (APP) results in a significant reduction in production of amyloid-β peptide (Aβ) peptides [12], whereas siRNA-mediated knockdown of ABCA7 increased Aβ production under similar experimental conditions [13]. In addition, phagocytic clearance of oligomeric Aβ was found to be impaired in ABCA7-deficient macrophages compared with wild-type (WT) macrophages [14].…”

“…An independent study using the same Abca7 null (Abca7 − / − ) mouse line but crossed with the TgCRND8 AD mouse model revealed an increase in the area of dense plaques at 18 weeks of age that the authors concluded was likely to be a reflection of the increased production of Aβ in the TgCRND8-Abca7 − / − mice [13]. It should be noted that even in the absence of the AD transgene expression, Abca7 − / − null mice were found to exhibit an age-dependent increase in the levels of the pathogenic (endogenous) Aβ42 peptide in the brain; assessed up to 6 months of age [13].…”

Novel Susceptibility Loci for Alzheimer's DXSisease

“…The ABCA7 gene, which was also identified in the largest GWAS to date performed in African Americans [20], encodes a member of the superfamily of ATP-binding cassette (ABC) transporters which traffic substrates across cell membranes and are largely involved in lipid transport and homeostasis. ABCA7 has been shown to directly mediate phagocytosis, membrane trafficking of APP and amyloid processing [50]. CD33, also called Siglec-3, is a transmembrane glycoprotein expressed on myeloid progenitor cells, mature monocytes and macrophages, that contains an extracellular immunoglobulin (Ig) V-set sialic-acid binding domain, an extracellular Ig C2-set domain and cytosolic immunoreceptor tyrosine-based inhibitory motifs.…”

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

“…The reduced capacity of ABCA7-depleted macrophages to phagocyte Aβ and its microglial expression in the brain suggest a role in Aβ clearance [90,92,93] . Recently, a negative role in APP processing and Aβ production through endocytosis regulation has also been shown [94] . Whatever the pathway involved (Aβ clearance or production), loss of ABCA7 function may result in an increased charge of Aβ peptide in the brain.…”