Dataset Information

Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.

ABSTRACT: Over 35% of the adult US population is obese. In turn, excess adiposity increases the risk of multiple complications including type 2 diabetes (T2D), insulin resistance, and cardiovascular disease; yet, obesity also independently heightens risk of Alzheimer's Disease (AD), even after adjusting for other important confounding risk factors including blood pressure, sociodemographics, cholesterol levels, smoking status, and Apolipoprotein E (ApoE) genotype. Among patients over the age of 65 with dementia, 37% have coexisting diabetes, and an estimated 7.3% of cases of AD are directly attributable to midlife obesity. Clusterin, also known as apolipoprotein J (ApoJ), is a multifunctional glycoprotein that acts as a molecular chaperone, assisting folding of secreted proteins. Clusterin has been implicated in several physiological and pathological states, including AD, metabolic disease, and cardiovascular disease. Despite long-standing interest in elucidating clusterin's relationship with amyloid beta (A?) aggregation/clearance and toxicity, significant knowledge gaps still exist. Altered clusterin expression and protein levels have been linked with cognitive and memory function, disrupted central nervous system lipid flux, as well as pathogenic brain structure; and its role in cardiometabolic disease suggests that it may be a link between insulin resistance, dyslipidemia, and AD. Here, we briefly highlight clusterin's relevance to AD by presenting existing evidence linking clusterin to AD and cardiometabolic disease, and discussing its potential utility as a biomarker for AD in the presence of obesity-related metabolic disease.

SUBMITTER: Bradley D

PROVIDER: S-EPMC7555556 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.

Bradley David D

Biomarker insights 20201012

Over 35% of the adult US population is obese. In turn, excess adiposity increases the risk of multiple complications including type 2 diabetes (T2D), insulin resistance, and cardiovascular disease; yet, obesity also independently heightens risk of Alzheimer's Disease (AD), even after adjusting for other important confounding risk factors including blood pressure, sociodemographics, cholesterol levels, smoking status, and Apolipoprotein E (ApoE) genotype. Among patients over the age of 65 with de ...[more]

PMID: 33110346

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Project description:The purpose of our study was to identify microRNAs (miRNAs) as early detectable peripheral biomarkers in Alzheimer's disease (AD). To achieve our objective, we assessed miRNAs in serum samples from AD patients and Mild cognitive impairment (MCI) subjects relative to healthy controls. We used Affymetrix microarray analysis and validated differentially expressed miRNAs using qRT-PCR. We further validated miRNA data using AD postmortem brains, amyloid precursor protein transgenic mice and AD cell lines. We identified a gradual upregulation of four miRNAs: miR-455-3p, miR-4668-5p, miR-3613-3p and miR-4674. A fifth miRNA, mir-6722, was down-regulated in persons with AD and mild cognitive impairment compared with controls. Validation analysis by qRT-PCR showed significant upregulation of only miR-455-3p (P?=?0.007) and miR-4668-5p (P?=?0.016) in AD patients compared with healthy controls. Furthermore, qRT-PCR analysis of the AD postmortem brains with different Braak stages also showed upregulation of miR-455-3p (P?=?0.016). However, receiver operating characteristic curves (ROC) curve analysis revealed a significant area under curve (AUC) value only for miR-455-3p in the serum (AUROC?=?0.79; P?=?0.015) and brains (AUROC?=?0.86; P?=?0.016) of AD patients. Expression analysis of amyloid precursor protein transgenic mice also revealed high level of mmu-miR-455-3p (P?=?0.004) in the cerebral cortex (AD-affected) region of brain and low in the non-affected area, i.e. cerebellum. Furthermore, human and mouse neuroblastoma cells treated with the amyloid-?(1-42) peptide also showed a similarly higher expression of miR-455-3p. Functional analysis of differentially expressed miRNAs via the miR-path indicated that miR-455-3p was associated in the regulation of several biological pathways. Genes associated with these pathways were found to have a crucial role in AD pathogenesis. An increase in miR-455-3p expression found in AD patients and A? pathologies unveiled its biomarker characteristics and a precise role in AD pathogenesis.

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Dataset Information

Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.

Publications

Clusterin as a Potential Biomarker of Obesity-Related Alzheimer's Disease Risk.

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