miR-125b Mediates Tau-induced Mitochondrial Dysfunction in a Cellular Model of Alzheimer's Disease.

MicroRNA (miRNA) dysregulation contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), but the role of specific miRNAs in tau-mediated toxicity remains unclear. Here, we investigated the contribution of hsa-miR-125b to tau-induced cellular dysfunction using a stable neuronal cell line overexpressing mutant tau (P301L). We found that hsa-miR-125b levels were significantly elevated in tau-expressing cells compared to controls. Using bioinformatic tools, we identified a strong enrichment of predicted hsa-miR-125b targets involved in mitochondrial function. We validated several of these targets by RT-qPCR and confirmed the downregulation of mitochondrial-related transcripts, including genes encoding components of complexes I, IV, and V of the electron transport chain. To assess functional consequences, we performed Seahorse metabolic flux analysis and observed impaired mitochondrial respiration in tau-overexpressing cells, including reduced basal respiration, ATP production, and spare respiratory capacity. Our findings demonstrate that hsa-miR-125b contributes to tau-induced mitochondrial dysfunction by repressing transcripts essential for mitochondrial homeostasis. We propose that hsa-miR-125b acts as a mechanistic link between tau pathology and metabolic impairment in AD and may represent a promising target for therapeutic intervention.