Combined Analysis Shows That Aβ42-Me3 Clumps Block Mitochondrial Cleanup in Early Alzheimer's Disease

Malic enzyme 3 (Me3) was upregulated and accumulated within mitochondria in APP/PS1 mice at ultra-early and early stages of Alzheimer's disease (3 and 6 months).

• Me3 colocalized with amyloid-β (Aβ42) and physically interacted with it in mitochondria, which is linked to oxidative stress and impaired removal of damaged mitochondria.
• Knockdown of Me3 resulted in reduced mitochondrial reactive oxygen species and improved mitochondrial structure.
• Mitophagy defects were alleviated in both cellular and mouse models following Me3 knockdown, showing statistical significance.
• The findings suggest that Me3 may play a role as a metabolic responder to Aβ-associated stress and contribute to early mitochondrial dysfunction in Alzheimer's disease.
• Further validation in human Alzheimer's disease samples is necessary.

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