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The role of clusterin in amyloid-?-associated neurodegeneration.

ABSTRACT: Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.To elucidate the relationship between clusterin, amyloid-? (A?), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF A?1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.Across all participants, we found a significant interaction between CSF clusterin and CSF A?1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF A?1-42-positive individuals but not among CSF A?1-42-negative individuals. In secondary analyses, we found significant interactions between CSF A?1-42 and CSF clusterin, as well as CSF A?1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.In nondemented older individuals, A?-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on A?-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on A?-associated volume loss.

SUBMITTER: Desikan RS

PROVIDER: S-EPMC4118752 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The role of clusterin in amyloid-β-associated neurodegeneration.

Desikan Rahul S RS Thompson Wesley K WK Holland Dominic D Hess Christopher P CP Brewer James B JB Zetterberg Henrik H Blennow Kaj K Andreassen Ole A OA McEvoy Linda K LK Hyman Bradley T BT Dale Anders M AM

JAMA neurology 20140201 2

<h4>Importance</h4>Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.<h4>Objective</h4>To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.<h4>Design, setting, and participants</h4>This longitudinal cohort inclu ...[more]

PMID: 24378367

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Project description:We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

Project description:Our understanding of the molecular processes underlying Alzheimer's disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating β-amyloid (Aβ) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in Aβ processing. Here we investigate how CLU mediates Aβ-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate Aβ-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to Aβ using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with Aβ25-35 peptides and Aβ1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following Aβ treatment. However, in CLU knockout neurons Aβ exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to Aβ in neurons with the CLU deletion. Four of the five genes previously identified as downstream to Aβ and Dickkopf-1 (DKK1) proteins in an Aβ-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in Aβ treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to Aβ compared to the wild type neurons supports the role of clusterin in Aβ-mediated AD pathogenesis.

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The role of clusterin in amyloid-?-associated neurodegeneration.

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The role of clusterin in amyloid-β-associated neurodegeneration.

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