Open Access

ARTICLE

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

ARTEM P. GUREEV¹, IRINA S. SADOVNIKOVA¹, EKATERINA V. CHERNYSHOVA¹, EKATERINA P. KRUTSKIKH¹, IRINA B. PEVZNER², LJUBAVA D. ZOROVA², VERONIKA V. NESTEROVA¹, POLINA I. BABENKOVA¹, EGOR Y. PLOTNIKOV^2,*

1 Department of Genetics, Cytology and Bioengineering, Voronezh State University, Voronezh, 396018, Russia
2 A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119899, Russia

* Corresponding Author: EGOR Y. PLOTNIKOV. Email:

(This article belongs to the Special Issue: Autophagy and Aging: Mechanisms and Implications)

BIOCELL 2025, 49(5), 873-892. https://doi.org/10.32604/biocell.2025.063557

Received 17 January 2025; Accepted 18 April 2025; Issue published 27 May 2025

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.

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