{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:10:40Z","timestamp":1791288640153,"version":"4.3.0"},"reference-count":57,"publisher":"Society for Neuroscience","issue":"13","license":[{"start":{"date-parts":[[2016,9,30]],"date-time":"2016-09-30T00:00:00Z","timestamp":1475193600000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,3,30]]},"abstract":"<jats:p>In Alzheimer's disease (AD), the accumulation and deposition of amyloid-\u03b2 (A\u03b2) peptides in the brain is a central event. A\u03b2 is cleaved from amyloid precursor protein (APP) by \u03b2-secretase and \u03b3-secretase mainly in neurons. Although mutations in<jats:italic>APP<\/jats:italic>,<jats:italic>PS1<\/jats:italic>, or<jats:italic>PS2<\/jats:italic>cause early-onset familial AD,<jats:italic>ABCA7<\/jats:italic>encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which its<jats:italic>loss-of-function<\/jats:italic>variants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (<jats:italic>Abca7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice. When bred to amyloid model APP\/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.<jats:italic>In vivo<\/jats:italic>microdialysis studies indicated that the clearance rate of A\u03b2 was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to A\u03b2 by increasing the levels of \u03b2-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2\u03b1 (eIF2\u03b1). In the brains of APP\/PS1;<jats:italic>Abca7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Gene variants in<jats:italic>ABCA7<\/jats:italic>encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-\u03b2 (A\u03b2) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain A\u03b2 deposition in amyloid AD model APP\/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and A\u03b2 production by increasing the levels of \u03b2-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the A\u03b2 clearance rate in APP\/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.<\/jats:p>","DOI":"10.1523\/jneurosci.3757-15.2016","type":"journal-article","created":{"date-parts":[[2016,3,30]],"date-time":"2016-03-30T21:56:03Z","timestamp":1459374963000},"page":"3848-3859","source":"Crossref","is-referenced-by-count":148,"title":["ABCA7 Deficiency Accelerates Amyloid-\u03b2 Generation and Alzheimer's Neuronal 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