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ABCA7 and Pathogenic Pathways of Alzheimer's Disease.

ABSTRACT: 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-? (A?) 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 A? 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 A? clearance pathway. Furthermore, ABCA7 deficiency results in accelerated A? 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.

SUBMITTER: Aikawa T

PROVIDER: S-EPMC5836046 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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ABCA7 and Pathogenic Pathways of Alzheimer's Disease.

Aikawa Tomonori T Holm Marie-Louise ML Kanekiyo Takahisa T

Brain sciences 20180205 2

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 ( ...[more]

PMID: 29401741

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Project description:BackgroundAlzheimer's disease (AD) is a pervasive age-related and highly heritable neurodegenerative disorder but has no effective therapy. The complex cellular microenvironment in the AD brain impedes our understanding of pathogenesis. Thus, a comprehensive investigation of cell type-specific responses in AD is crucial to provide precise molecular and cellular targets for therapeutic development.MethodsHere, we integrated analyzed 4,441 differentially expressed genes (DEGs) that were identified from 263,370 single-cells in cortex samples by single-nucleus RNA sequencing (snRNA-seq) between 42 AD-pathology subjects and 39 normal controls within 3 studies. DEGs were analyzed in microglia, astrocytes, oligodendrocytes, excitatory neurons, inhibitory neurons, and endothelial cells, respectively. In each cell type, we identified both common DEGs which were observed in all 3 studies, and overlapping DEGs which have been seen in at least 2 studies. Firstly, we showed the common DEGs expression and explained the biological functions by comparing with existing literature or multil-omics signaling pathways knowledgebase. We then determined the significant modules and hub genes, and explored the biological processes using the overlapping DEGs. Finally, we identified the common and distinct dysregulated pathways using overall DEGs and overlapping DEGs in a cell type-specific manner.ResultsUp-regulated LINGO1 has been seen in both oligodendrocytes and excitatory neurons across 3 studies. Interestingly, genes enriched in the mitochondrial module were up-regulated across all cell types, which indicates mitochondrial dysfunction in the AD brain. The estrogen signaling pathway seems to be the most common pathway that is disrupted in AD.ConclusionTogether, these analyses provide detailed information of cell type-specific and overall transcriptional changes and pathways underlying the human AD-pathology. These findings may provide important insights for drug development to tackle this disease.

Project description:Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Dataset Information

ABCA7 and Pathogenic Pathways of Alzheimer's Disease.

Publications

ABCA7 and Pathogenic Pathways of Alzheimer's Disease.

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