miR-769-5p as a Novel Biomarker and Functional Mediator in Alzheimer's Disease: Targeting CREB5 to Alleviate...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with mild cognitive impairment (MCI) as its critical prodromal stage. Identifying reliable biomarkers to distinguish AD from MCI is key for early intervention. This study explored miR-769-5p's potential as a diagnostic biomarker for AD and its mechanism, especially its links to oxidative stress and target gene CREB5. Serum miR-769-5p and CREB5 levels were measured via qRT-PCR. Cellular models used Aβ₄₂-treated SH-SY5Y cells, validated by confirming key AD pathologies including increased Tau phosphorylation. Functional/mechanistic assessments employed CCK-8, MDA, SOD, and dual-luciferase reporter assays. Clinically, multivariate logistic regression identified miR-769-5p as a strong independent protective factor (OR = 0.029, p < 0.001). miR-769-5p was downregulated in AD versus MCI and accurately distinguished them (AUC = 0.919). In Aβ-treated cells, miR-769-5p overexpression reduced Aβ-induced proliferation suppression and oxidative stress (lower MDA, higher SOD, all p < 0.01), while inhibition worsened damage. CREB5, a direct miR-769-5p target, was upregulated in AD. Functionally, rescue assays confirmed CREB5 overexpression reversed miR-769-5p mimic's protection. In conclusion, serum miR-769-5p is a promising biomarker for AD-MCI distinction and may protect against AD by targeting CREB5 to mitigate oxidative stress.