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risk, however, the mechanisms by which ABCA7 may control AD risk remain to be fully elucidated. Based on previous research suggesting that certain ABC transporters may play a role in the regulation of neurogenesis, we conducted a study of cell proliferation and neurogenic potential using cellular bromodeoxyuridine (BrdU) incorporation and doublecortin (DCX) immunostaining in adult Abca7 deficient mice and wild-type-like (WT) littermates. In the present study counting of BrdU-positive and DCX-positive cells in an established adult neurogenesis site in the dentate gyrus (DG) indicated there were no significant differences when WT and Abca7 deficient mice were compared. We also measured the area occupied by immunohistochemical staining for BrdU and DCX in the DG and the subventricular zone (SVZ) of the same mice and this confirmed that ABCA7 does not play a significant role in the regulation of cell proliferation or neurogenesis in the adult mouse.

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n Icelanders (odds ratio (OR) = 2.12, P = 2.2 x 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 x 10(-15)).

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AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants 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 (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Abeta was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Abeta by increasing the levels of beta-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 2alpha (eIF2alpha). In the brains of APP/PS1;Abca7(-/-)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. SIGNIFICANCE STATEMENT: Gene variants inABCA7encoding 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-beta (Abeta) 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 Abeta deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Abeta production by increasing the levels of beta-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Abeta clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.

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ABCA7 in this cohort with the aim to directly detect rare and common variations in this gene associated with Alzheimer's disease pathogenesis. METHODS: We did massive parallel resequencing of ABCA7 after HaloPlex target enrichment of the exons, introns, and regulatory regions in 772 unrelated patients with Alzheimer's disease (mean age at onset 74.6 years [SD 8.9]) recruited at two memory clinics in Flanders, Belgium, and 757 geographically matched community-dwelling controls (mean age at inclusion 73.9 years [8.0]). After bioinformatic processing, common variants were analysed with conditional logistic regression and rare variant association analysis was done in Variant Association Tools. To explore an observed founder effect, additional unrelated patients with Alzheimer's disease (n=183, mean age at onset 78.8 years [SD 6.0]) and control individuals (n=265, mean age at inclusion 56.9 years [10.8]) from the same cohort who had not been included in massive parallel resequencing because of insufficient biosamples were screened for the ABCA7 frameshift mutation Glu709fs with Sanger sequencing. The effect of loss-of-function mutations on ABCA7 expression was investigated with quantitative real-time PCR in post-mortem brains of patients (n=3) and control individuals (n=4); nonsense mediated mRNA decay was investigated in lymphoblast cell lines from three predicted loss-of-function mutation carriers from the cohort of 772 patients with Alzheimer's disease. FINDINGS: An intronic low-frequency variant rs78117248 (minor allele frequency 3.8% in 58 patients with Alzheimer's disease and in controls 1.8% in 28 controls) showed strongest association with Alzheimer's disease (odds ratio 2.07, 95% CI 1.31-3.27; p=0.0016), and remained significant after conditioning for the GWAS top single nucleotide polymorphisms rs3764650, rs4147929, and rs3752246 (2.00, 1.22-3.26; p=0.006). We identified an increased frequency of predicted loss-of-function mutations in the patients compared with the controls (relative risk 4.03, 95% CI 1.75-9.29; p=0.0002). One frameshift mutation (Glu709fs) showed a founder effect in the study population, and was found to segregate with disease in a family with autosomal dominant inheritance of Alzheimer's disease. Expression of ABCA7 was reduced in the two carriers of loss-of-function mutations found only in patients with Alzheimer's disease (Glu709fs and Trp1214*) compared with four non-carrier controls (relative expression 0.45, 95% CI 0.25-0.84; p=0.002) and in lymphoblast cell lines from three carriers of Glu709fs compared with those from two non-carrier controls. INTERPRETATION: We propose that a low-frequency variant can explain the association between ABCA7 and Alzheimer's disease, and the evidence of loss-of-function mutations in this risk gene suggests that partial loss-of-function of ABCA7 could be a potential pathogenetic mechanism of Alzheimer's disease. FUNDING: Belgian Science Policy Office Interuniversity Attraction Poles program P7/16, Alzheimer Research Foundation, King Baudouin Foundation AB Fund, Methusalem Excellence Program initiative of the Flemish Government, Flanders Impulse Program on Networks for Dementia Research, Research Foundation Flanders, Agency for Innovation by Science and Technology Flanders, University of Antwerp Research Fund, and European Union's Seventh Framework Programme for Research, Technological development and Demonstration (AgedBrainSYSBIO).