Tau Protein Aggregation and Mitochondrial Dysfunction in Alzheimer's Disease: A Novel Therapeutic Target via Mitophagy Enhancement

Abstract

Alzheimer's disease (AD) is characterized by progressive neurodegeneration associated with accumulation of tau protein aggregates and mitochondrial dysfunction. However, the molecular link between tau pathology and mitochondrial impairment remains poorly understood. This study elucidates a novel mechanism by which hyperphosphorylated tau disrupts mitochondrial quality control through inhibition of PINK1/Parkin-mediated mitophagy. Using CRISPR/Cas9-generated tau P301S mutation knock-in mice and human iPSC-derived neurons, we demonstrate that pathological tau directly binds to mitochondrial outer membrane proteins, preventing Parkin recruitment and subsequent mitophagy initiation. Confocal microscopy and transmission electron microscopy revealed accumulation of damaged mitochondria with disrupted cristae structure in tau-expressing neurons. Metabolic flux analysis showed significant reduction in ATP production and increased reactive oxygen species generation. Remarkably, pharmacological enhancement of mitophagy using Urolithin A treatment rescued mitochondrial function, reduced tau aggregation, and improved cognitive performance in AD mice models. Immunohistochemistry of postmortem human AD brain tissue validated the correlation between tau burden and mitophagy impairment. These findings identify mitophagy enhancement as a promising therapeutic strategy targeting both tau pathology and mitochondrial dysfunction in Alzheimer's disease.