Dysregulation of Nrf2/ARE pathway and mitochondrial DNA damage in aging and Alzheimer’s-associated cognitive decline

Abstract

Background: Mitochondrial dysfunction represents a critical link between physiological aging and Alzheimer’s disease (AD), though the specific mechanisms driving pathological cognitive decline remain unclear. In this study, we investigated how Nrf2/ARE pathway suppression and mitochondrial DNA (mtDNA) damage contribute to accelerated memory impairment in APP/PS1 mice compared to age-matched wild-type (C57BL/6) controls. 

Methods: The Barnes test was used to assess cognitive function. We also analysed the level of oxidative damage to mitochondrial DNA (mtDNA) in various areas of the brain, including the cerebellum and midbrain. We evaluated the activity of the Nrf2/ARE cytoprotective pathway, as well as the expression of antioxidant genes involved in H₂O₂ utilisation and genes associated with DNA repair. Additionally, we investigated the level of the pro-inflammatory cytokine TNFα and changes in the composition of the intestinal microbiota.

Results: Cognitive impairments were observed in transgenic mice at 4 and 8 months of age, as evidenced by an increase in the time required to find the exit. Transgenic mice showed a significant accumulation of oxidative damage to mitochondrial DNA (mtDNA) in certain areas of the brain, primarily in the cerebellum and partially in the midbrain. Compared to C57BL/6 mice, APP/PS1 mice showed reduced expression of antioxidant genes involved in H₂O₂ utilisation, as well as genes associated with DNA repair. These mitochondrial dysfunctions may contribute to cerebellar dysfunction. We found increased expression of the pro-inflammatory cytokine TNFα, as well as some signs of changes in the composition of the gut microbiota.

Conclusion: Our findings identify mitochondrial maintenance, particularly via the Nrf2/ARE pathway, as a promising target for interventions aimed at mitigating pathological aging while preserving normal cognitive function.

Keywords: Alzheimer's disease, cognitive impairments, Barnes maze, APP/PS1 mouse strain, Nrf2/ARE signal pathway