The Alzheimer's disease GWAS risk alleles in the ABCA7 promoter and 5' region reduce ABCA7 expression.
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ABSTRACT:
SUBMITTER: Lyssenko NN
PROVIDER: S-EPMC9388598 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
Publications
The Alzheimer's disease GWAS risk alleles in the ABCA7 promoter and 5' region reduce ABCA7 expression.
Lyssenko Nicholas N NN Shi Xinghua X Praticò Domenico D
Acta neuropathologica 20220627 3
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Project description:Genome-wide association studies (GWAS) have implicated a series of single nucleotide polymorphisms (SNPs) in Alzheimer's disease (AD) risk. Elucidating the function of these SNPs is critical to identify the underlying pathways and, potentially, novel therapeutic agents. SNPs within the gene ATP binding cassette A7 (ABCA7) reached significance in these studies, warranting investigation into their actions. Here, we analyzed ABCA7 expression in a set of human brain samples as a function of AD-associated SNPs and AD status. We report that the rs3764650T allele that decreases AD risk is associated with increased ABCA7 expression. However, ABCA7 expression is increased in AD individuals. We interpret our findings as suggesting a model wherein increased ABCA7 expression reduces AD risk and that the increased ABCA7 observed in AD reflects an inadequate compensatory change.
| S-EPMC3863933 | biostudies-literature
Project description:African American/Black adults are twice as likely to have Alzheimer's disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and 'omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.
| S-EPMC10984370 | biostudies-literature
Project description:Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA.
| S-EPMC5890296 | biostudies-literature
Project description:The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer’s disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.
2025-03-13 | GSE288170 | GEO
Project description:The ATP-binding cassette (ABC) reporter family functions to regulate the homeostasis of phospholipids and cholesterol in the central nervous system, as well as peripheral tissues. ABCA7 belongs to the A subfamily of ABC transporters, which shares 54% sequence identity with ABCA1. While ABCA7 is expressed in a variety of tissues/organs, including the brain, recent genome-wide association studies (GWAS) have identified ABCA7 gene variants as susceptibility loci for late-onset Alzheimer's disease (AD). More important, subsequent genome sequencing analyses have revealed that premature termination codon mutations in ABCA7 are associated with the increased risk for AD. Alzheimer's disease is a progressive neurodegenerative disease and the most common cause of dementia, where the accumulation and deposition of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain trigger the pathogenic cascade of the disease. In consistence with human genetic studies, increasing evidence has demonstrated that ABCA7 deficiency exacerbates Aβ pathology using in vitro and in vivo models. While ABCA7 has been shown to mediate phagocytic activity in macrophages, ABCA7 is also involved in the microglial Aβ clearance pathway. Furthermore, ABCA7 deficiency results in accelerated Aβ production, likely by facilitating endocytosis and/or processing of APP. Taken together, current evidence suggests that ABCA7 loss-of-function contributes to AD-related phenotypes through multiple pathways. A better understanding of the function of ABCA7 beyond lipid metabolism in both physiological and pathological conditions becomes increasingly important to explore AD pathogenesis.
| S-EPMC5836046 | biostudies-literature
Project description:Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3-24.2)], and VNTR length inversely correlated with amyloid β1-42 in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular-which is formed through exon 19 skipping-lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD.
| S-EPMC5954066 | biostudies-literature
Project description:ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer's disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-? peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important in AD context because it is the primary producer of leptin, which is a hormone that is known to modulate AD neuropathology. WAT in male Abca7-/- mice was not altered. The pathological link between ABCA7 and WAT that impacts on AD is unknown. Our transcription analysis revealed that lipin-1 expression was significantly upregulated in female Abca7-/- mice, indicating that ABCA7 affects WAT development. The circulating leptin level was significantly reduced in female Abca7-/- mice without any change in WAT leptin mRNA or protein expression, indicating that ABCA7 does not affect leptin production, but alters the circulating leptin level indirectly by affecting WAT development. Insulin is a key hormone that regulates WAT development, i.e., adipogenesis, and it was significantly reduced in female Abca7-/- mice. These data when put together suggest that ABCA7 plays a role in regulating WAT development and consequently circulating leptin levels, which are known to modulate AD neuropathology.
| S-EPMC6159609 | biostudies-other
Project description:Genetic studies have provided the best evidence for cause and effect relationships in Alzheimer's disease (AD). Indeed, the identification of deterministic mutations in the APP, PSEN1 and PSEN2 genes and subsequent preclinical studies linking these mutations to alterations in Aβ production and aggregation have provided pivotal support for the amyloid cascade hypothesis. In addition, genetic, pathologic and biological studies of APOE have also indicated that the genetic risk for AD associated with APOE4 can be attributed, at least in part, to its pro-amyloidogenic effect on Aβ. In recent years a number of SNPs that show unequivocal genome-wide association with AD risk have implicated novel genetic loci as modifiers of AD risk. However, the functional implications of these genetic associations are largely unknown. For almost all of these associations, the functional variants have not been identified. Very recently, two large consortiums demonstrated that rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer significant risk for AD. TREM2 is a type 1 membrane receptor protein primarily expressed on microglia in the central nervous system that has been shown to regulate phagocytosis and activation of monocytes. Previously it had been shown that homozygous loss of function mutations in TREM2 cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu Hakola disease) and also a pure form of early-onset dementia. The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis.
| S-EPMC3706774 | biostudies-literature
Project description:The adenosine triphosphate-binding cassette subfamily A member 7 gene (ABCA7) is associated with Alzheimer's disease (AD) in large genome-wide association studies. Targeted sequencing of ABCA7 suggests a role for rare premature termination codon (PTC) mutations in AD, with haploinsufficiency through nonsense-mediated mRNA decay as a plausible pathogenic mechanism. Since other classes of rare variants in ABCA7 are poorly understood, we investigated the contribution and pathogenicity of rare missense, indel and splice variants in ABCA7 in Belgian AD patient and control cohorts. We identified 8.36% rare variants in the patient cohort versus 6.05% in the control cohort. For 10 missense mutations identified in the Belgian cohort we analyzed the pathogenetic effect on protein localization in vitro using immunocytochemistry. Our results demonstrate that rare ABCA7 missense mutations can contribute to AD by inducing protein mislocalization, resulting in a lack of functional protein at the plasma membrane. In one pedigree, a mislocalization-inducing missense mutation in ABCA7 (p.G1820S) co-segregated with AD in an autosomal dominant inheritance pattern. Brain autopsy of six patient missense mutation carriers showed typical AD neuropathological characteristics including cerebral amyloid angiopathy type 1. Also, among the rare ABCA7 missense mutations, we observed mutations that affect amino acid residues that are conserved in ABCA1 and ABCA4, of which some correspond to established ABCA1 or ABCA4 disease-causing mutations involved in Tangier or Stargardt disease.
| S-EPMC8973822 | biostudies-literature
Project description:We propose the altered lipidostasis hypothesis of Alzheimer's disease (AD). It holds that vulnerable neurons of the entorhinal region generate a neurodegenerative lipid during normal function, adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) protects from AD pathogenesis by removing it out of the cell, generation of the lipid increases with age, and the minimal amount of ABCA7 needed to dispose of the rising volumes of the lipid also increases with age. A survey of ABCA7 protein levels in the hippocampus or parietal cortex of 123 individuals with or without AD neuropathology showed that individuals with low ABCA7 developed AD neuropathology at a younger age, those with intermediate ABCA7 developed it later, and individuals who developed it very late had high ABCA7, the same as the youngest controls. ABC transporters closely similar to ABCA7 protect cells by removing toxic lipids. ABCA7 may have analogous functions. The hypothesis predicts lipidosis and membrane protein dysfunction in neurons with low ABCA7. Further work will identify the neurodegenerative lipid and determine approaches to exploit ABCA7 for therapeutic purposes.
| S-EPMC7986801 | biostudies-literature