Dataset Information

Influence of Coding Variability in APP-A? Metabolism Genes in Sporadic Alzheimer's Disease.

ABSTRACT: The cerebral deposition of A?42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-A? metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, A? degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4

SUBMITTER: Sassi C

PROVIDER: S-EPMC4889076 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

Sassi Celeste C Ridge Perry G PG Nalls Michael A MA Gibbs Raphael R Ding Jinhui J Lupton Michelle K MK Troakes Claire C Lunnon Katie K Al-Sarraj Safa S Brown Kristelle S KS Medway Christopher C Lord Jenny J Turton James J Morgan Kevin K Powell John F JF Kauwe John S JS Cruchaga Carlos C Bras Jose J Goate Alison M AM Singleton Andrew B AB Guerreiro Rita R Hardy John J

PloS one 20160601 6

The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in the ...[more]

PMID: 27249223

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Project description:Clusterin, also known as apoJ, is a lipoprotein abundantly expressed within the CNS. It regulates Aβ fibril formation and toxicity and facilitates amyloid-β (Aβ) transport across the blood-brain barrier. Genome-wide association studies have shown variations in the clusterin gene (CLU) to influence the risk of developing sporadic Alzheimer's disease (AD). To explore whether clusterin modulates the regional deposition of Aβ, we measured levels of soluble (NP40-extracted) and insoluble (guanidine-HCl-extracted) clusterin, Aβ40 and Aβ42 by sandwich ELISA in brain regions with a predilection for amyloid pathology-mid-frontal cortex (MF), cingulate cortex (CC), parahippocampal cortex (PH), and regions with little or no pathology-thalamus (TH) and white matter (WM). Clusterin level was highest in regions with plaque pathology (MF, CC, PH and PC), approximately mirroring the regional distribution of Aβ. It was significantly higher in AD than controls, and correlated positively with Aβ42 and insoluble Aβ40. Soluble clusterin level rose significantly with severity of cerebral amyloid angiopathy, and in MF and PC regions was highest in APOE ɛ4 homozygotes. In the TH and WM (areas with little amyloid pathology) clusterin was unaltered in AD and did not correlate with Aβ level. There was a significant positive correlation between the concentration of clusterin and the regional levels of insoluble Aβ42; however, the molar ratio of clusterin : Aβ42 declined with insoluble Aβ42 level in a region-dependent manner, being lowest in regions with predilection for Aβ plaque pathology. Under physiological conditions, clusterin reduces aggregation and promotes clearance of Aβ. Our findings indicate that in AD, clusterin increases, particularly in regions with most abundant Aβ, but because the increase does not match the rising level of Aβ42, the molar ratio of clusterin : Aβ42 in those regions falls, probably contributing to Aβ deposition within the tissue.

Dataset Information

Influence of Coding Variability in APP-A? Metabolism Genes in Sporadic Alzheimer's Disease.

Publications

Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

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