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MicroRNA-455-3p as a potential peripheral biomarker for Alzheimer's disease
Subodh Kumar1, Murali Vijayan1, P Hemachandra Reddy1,2,3,4,5,6
1Biomarker Unit, Garrison Institute on Aging.
Abstract:
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-β(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 Aβ pathologies unveiled its biomarker characteristics and a precise role in AD pathogenesis.
Insights
Researchers identified miR-455-3p as a promising biomarker for Alzheimer's disease (AD). This microRNA shows increased levels in AD patients' serum and brain tissue, suggesting its potential for early detection and understanding AD pathogenesis.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Alzheimer's disease (AD) poses a significant global health challenge.
- Early and accurate diagnosis of AD is crucial for effective management.
- Identifying reliable peripheral biomarkers for AD remains a key research objective.
Purpose of the Study:
- To identify specific microRNAs (miRNAs) that can serve as early detectable peripheral biomarkers for Alzheimer's disease (AD).
- To investigate the expression patterns of miRNAs in serum and brain samples from AD patients, mild cognitive impairment (MCI) subjects, and healthy controls.
Main Methods:
- Serum samples from AD patients, MCI subjects, and controls were analyzed using Affymetrix microarray.
- Differentially expressed miRNAs were validated via quantitative real-time PCR (qRT-PCR).
- Further validation involved postmortem AD brains, amyloid precursor protein transgenic mice, and AD cell lines.
Main Results:
- Four miRNAs (miR-455-3p, miR-4668-5p, miR-3613-3p, miR-4674) showed gradual upregulation, while miR-6722 was downregulated in AD and MCI.
- qRT-PCR confirmed significant upregulation of miR-455-3p and miR-4668-5p in AD patients.
- miR-455-3p demonstrated significant diagnostic potential with high area under the curve (AUC) values in both serum and brain tissue analyses.
- Increased miR-455-3p expression was observed in AD-affected brain regions of mice and in human/mouse neuroblastoma cells treated with amyloid-beta peptide.
Conclusions:
- miR-455-3p is a significantly upregulated miRNA in Alzheimer's disease patients, detectable in both serum and brain tissue.
- The expression pattern of miR-455-3p suggests its role as a potential early diagnostic biomarker for AD.
- Functional analysis indicates miR-455-3p's involvement in biological pathways crucial to AD pathogenesis, highlighting its potential therapeutic relevance.