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Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue.

ABSTRACT: Genome-wide association studies have pointed to clusterin (apolipoprotein J) as being linked to the occurrence of Alzheimer's disease (AD); studies have identified the protein as a possible biomarker. The association between clusterin and senile plaques in AD brain is well known, and clusterin levels in AD brain are 40% higher than that in control subjects. The present study investigates, immunohistochemically, the association between clusterin and Aβ peptides in AD and control cortex. A unique and specific association between clusterin and Aβ40 was observed in plaques in the cerebral cortex from AD subjects in that only plaques that contained Aβ40 showed clusterin immunoreactivity, while the many plaques with Aβ42 alone lacked clusterin labeling. Cerebrovascular Aβ in AD brain generally lacked Aβ42 but was positively labeled by both the Aβ40 and the clusterin antibodies. In control subjects, however, Aβ40 was absent from plaques, although very occasional plaques were found to be labeled by both the Aβ42 and the clusterin antibodies. Overall, in AD, but not aged control brain, clusterin was associated specifically with the Aβ40 form of Aβ in the brain. The lack of clusterin in association with Aβ42 may be a significant feature in neuronal loss and neurodegeneration in the disease state.

SUBMITTER: Howlett DR

PROVIDER: S-EPMC8029492 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIt has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD.MethodsHere, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region.ResultsWe found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum.ConclusionOur comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.

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Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue.

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