Resveratrol Preserves Mitochondrial DNA Integrity and Long-Term Memory without Decreasing Amyloid-β Levels in Alzheimer’s Disease Mouse Models

Abstract

Background: Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Resveratrol is a promising compound for the treatment of various neurodegenerative diseases, including AD. Aims: To investigate mitochondrial damage and the effects of resveratrol on inflammation, cognitive function, and mitochondrial quality control in APP/PS1 mice. Methods: Comparative analysis of mitochondrial DNA (mtDNA) damage was conducted between 10-month-old APP/PS1 mice and age-matched C57BL/6 mice. Assessments included measurement of amyloid-β levels, inflammatory markers, swimming distance in the Morris water maze, and gut microbiome composition. Resveratrol’s effects on cytokine expression, mtDNA levels in plasma, and activation of Nuclear factor erythroid 2-related factor 2/Antioxidant response element (Nrf2/ARE) and phosphoinositide 3-kinase/protein kinase B (also known as Akt)/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) signaling pathways were also evaluated. Results: APP/PS1 mice exhibited significantly increased mtDNA damage in the prefrontal cortex, midbrain, and cerebellum, alongside higher amyloid-β levels and inflammatory markers. Resveratrol treatment led to reduced expression of pro-inflammatory cytokines, a decrease in Proteobacteria levels, and lower cell-free mtDNA in plasma. Partial improvement in long-term spatial memory was observed in APP/PS1 mice following resveratrol treatment, likely due to its anti-inflammatory properties. Activation of the Nrf2/ARE signaling pathway and markers of PI3K/Akt/mTORC1 axis activation were noted, with the latter regulating long-term potentiation. Conclusion: Resveratrol demonstrates potential in mitigating inflammation and improving mitochondrial quality control in APP/PS1 mice, but it does not reduce amyloid-β levels, highlighting the complexity of AD pathology and the need for further research.