Deletion of<i>Abca7</i>Increases Cerebral Amyloid-β Accumulation in the J20 Mouse Model of Alzheimer's Disease

Kim, Woojin Scott; Liu, Hongyun; Ruberu, Kalani; Chan, Sharon; Elliott, David A.; Low, Jac Kee; Cheng, David; Karl, Tim; Garner, Brett

doi:10.1523/jneurosci.4165-12.2013

Cited by 179 publications

(174 citation statements)

References 44 publications

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“…In addition, phagocytic clearance of oligomeric Aβ was found to be impaired in ABCA7-deficient macrophages compared with wild-type (WT) macrophages [14]. In general agreement with these cell culture studies, work in AD mouse models has also provided evidence supporting a role for ABCA7 in amyloid homoeostasis.…”

Section: Introductionsupporting

confidence: 67%

“…In general agreement with these cell culture studies, work in AD mouse models has also provided evidence supporting a role for ABCA7 in amyloid homoeostasis. In the J20 AD transgenic mouse model, deletion of ABCA7 led to a doubling of insoluble Aβ levels and amyloid plaques in mice assessed at 17 months of age [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].…”

Section: Introductionmentioning

confidence: 99%

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Abca7 deletion does not affect adult neurogenesis in the mouse

Karl

Garner

2016

Bioscience Reports

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SynopsisATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) have identified ABCA7 single nucleotide polymorphisms (SNPs) that increase Alzheimer's disease (AD) 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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Section: Introductionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Abca7 deletion does not affect adult neurogenesis in the mouse

Karl

Garner

2016

Bioscience Reports

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“…In addition to nonsynonymous ABCA7 variants, we observed a splice site, a stop mutation, and frameshift deletions, suggesting a loss‐of‐function mechanism associated with LOAD. Our recent functional studies of ABCA7 strongly support such a possibility,29, 30 because suppression of ABCA7 in vitro and in vivo resulted in an elevation of amyloid production. The complex function of ABCA7 includes mediation of the biogenesis of high‐density lipoprotein with cellular lipid and helical apolipoproteins,31 as well as function in apolipoprotein‐mediated phospholipid and cholesterol efflux from cells 32.…”

Section: Discussionmentioning

confidence: 76%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

133

117

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ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

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“…Kim et al found that ABCA7 knockout mice crossed with J20 amyloidogenic mice had double the amount of insoluble amyloid‐ β concentration and plaque levels in the brain compared to J20 mice 24. The ability to phagocytose amyloid‐ β ‐oligomers in isolated microglia and macrophages was reduced in ABCA7 knockout mice compared to wild‐type mice 12.…”

Section: Discussionmentioning

confidence: 99%

“…ABCA7 is highly expressed in brain tissue,9, 21, 22 most abundant in microglia and oligodendrocytes 7, 23. Previous studies comparing ABCA7 knock‐out mice with wild‐type mice or J20 amyloidogenic mice demonstrate that ABCA7 is involved in clearance of amyloid‐ β in the brain through phagocytosis 12, 24. Furthermore, early studies on ABCA7 explored lipid efflux capacities and suggested that ABCA7 contributes to phospholipid and cholesterol transport 8, 9, 10, 21, 25, 26, 27.…”

Section: Introductionmentioning

confidence: 99%

ABCA7 and risk of dementia and vascular disease in the Danish population

Kjeldsen

Tybjærg‐Hansen

Nordestgaard

et al. 2017

Ann Clin Transl Neurol

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Objective ATP‐binding‐cassette transporter A7(ABCA7) is suggested to be involved in lipid transport as well as in phagocytosis of amyloid‐β in the brain. We tested the hypothesis that a common genetic variant in ABCA7 is associated with dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels in the general population, independent of the common apolipoprotein E(APOE) genotype.MethodsFor this purpose, we genotyped a common genetic variant in ABCA7, identified in genome‐wide‐association‐studies of Alzheimer's disease, in 104,258 individuals from the Danish general population, and also meta‐analyzed our results with publicly available consortia data.ResultsMultifactorially adjusted hazard ratios for Alzheimer's disease were 1.07 (95% confidence interval:0.93–1.23) and 1.72 (1.24–2.40) for GA and AA versus GG genotype. Results were similar after APOE genotype adjustment and when only APOE ɛ33 carriers were studied. Including 178,304 individuals, the meta‐analyzed odds ratio for Alzheimer's disease per one allele ABCA7 rs4147929 increase was 1.15 (1.12–1.18). ABCA7 genotype was not convincingly associated with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, or with lipid levels. Including 288,563 individuals, meta‐analyzed odds ratios for ischemic heart disease per one allele ABCA7 rs4147929 increase was 1.01 (0.99–1.03).InterpretationA common genetic variant in ABCA7 was associated with high risk of Alzheimer's disease independent of APOE genotype. The lack of association with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels suggests that ABCA7 is not important for atherosclerosis. Thus, our findings support the suggested role of ABCA7 in Alzheimer's disease pathology and phagocytic clearance of amyloid‐β in the brain.

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Deletion ofAbca7Increases Cerebral Amyloid-β Accumulation in the J20 Mouse Model of Alzheimer's Disease

Cited by 179 publications

References 44 publications

Abca7 deletion does not affect adult neurogenesis in the mouse

Abca7 deletion does not affect adult neurogenesis in the mouse

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

ABCA7 and risk of dementia and vascular disease in the Danish population

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