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 A42 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-...
Sarco/endoplasmic reticulum (SR/ER) Cadynamics. F-L577 will be useful for future studies on Ca 2؉ signaling involving SERCA2a activity. Intracellular Ca2ϩ plays a pivotal role in controlling numerous cellular processes such as exocytosis, gene transcription, cell proliferation, muscle contraction, and cell survival (1). The level of intracellular Ca 2ϩ is determined by the balance between the influx that introduces Ca 2ϩ into the cytoplasm and the efflux that removes it from the cytoplasm. The key molecules involved in the regulation of intracellular Ca 2ϩ such as channels, pumps, and exchangers have been identified (2). Channels in the plasma membrane and sarco/endoplasmic reticulum (SR/ER) 8 membrane are responsible for the Ca 2ϩ influx, whereas pumps and exchangers carry out the Ca 2ϩ efflux. SR/ER Ca 2ϩ -ATPase (SERCA) is a Ca 2ϩ pump that transfers Ca 2ϩ from the cytosol to the lumen of the SR/ER at the expense of ATP hydrolysis (3). SERCA functions to determine the resting level of intracellular Ca 2ϩ (4) and to control the spatiotemporal profile of Ca 2ϩ transients and the frequency of Ca 2ϩ oscillations (5). Impairment of SERCA causes Ca 2ϩ homeostatic dysfunction, resulting in several important disease states such as heart failure, hypertension, diabetes, and Alzheimer disease (6).The SERCA family consists of three isoforms and their splicing variants (SERCA1a, -1b, -2a, -2b, -3a, -3b, and -3c). The molecular masses of SERCA isoforms range from 105 to 115 kDa. Each SERCA isoform consists of four distinct functional domains, namely the nucleotide-binding, phosphorylation, actuator, and transmembrane domains (7). The three-dimensional structures of different conformational states of SERCA1a have been defined by x-ray crystallography (8), and structural models for the catalytic cycle of SERCA are well established (9).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.