Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease

Abstract

Dysfunctional mitophagy is a key component of Alzheimers disease (AD) pathology, yet direct in vivo evidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model (APP/PSEN1/mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls. Abnormal mitochondrial accumulation in dystrophic neurites, defective mitophagy, and impaired lysosomal function disrupted proper mitochondrial degradation, resulting in excessive mitochondria accumulation both within and outside autophagic vesicles. The resulting intensive mitochondria-containing neurites coalesce into MPs, which co-develop with amyloid plaques to form mixed plaques. These findings establish MPs as novel pathological entity and a promising therapeutic target in AD.