Multi-Omics Analysis Reveals That Aβ42- Me3 Co-Aggregation Induces Mitophagy Blockade in Early Stages of Alzheimer's Disease.

Mitochondrial dysfunction is one of the earliest pathological features of Alzheimer's disease (AD), preceding overt neurodegeneration and cognitive decline. Amyloid-β (Aβ) accumulation has long been considered a central pathogenic event in AD, yet how Aβ toxicity is mechanistically linked to mitochondrial impairment during early disease stages remains incompletely understood. To address this, we combined multi-omics with in vivo and in vitro genetic interventions. Here, we show that malic enzyme 3 (Me3) links Aβ aggregation to mitochondrial dysfunction in APP/PS1 mice and neuronal cells. At ultra-early and early AD stages (3 and 6 months), Me3 was upregulated and accumulated within mitochondria, where it colocalized with Aβ42 and physically interacted with it, an association linked to oxidative stress and impaired mitophagy. Knockdown of Me3 reduced mitochondrial reactive oxygen species, improved mitochondrial morphology, and alleviated mitophagy defects in both cellular and mouse models, with statistical significance across these functional measurements (p < 0.05). These results suggest that Me3 functions not only as a metabolic responder to Aβ-associated stress but also as a contributor to early mitochondrial pathology. By identifying the Aβ-Me3 axis, this study provides mechanistic insight into early mitochondrial dysfunction in AD, while further validation in human AD samples remains necessary.