Mid-life exposure to chronic stress accelerates cerebrovascular dysfunction and upregulates oxidative stress in Alzheimer's disease mice.

BackgroundThis study uses the Unpredictable Chronic Mild Stress (UCMS) model to investigate the effects of mid-life stress (MLS) on vascular and neurobiological changes in triple transgenic Alzheimer's disease mice (3xTg-AD) during critical developmental stages.ObjectiveTo investigate how mid-life stress (MLS) affects cerebrovascular function and AD progression. We hypothesize that chronic stress in 3xTg-AD mice will accelerate cerebrovascular dysfunction and, subsequently, the associated AD pathology.MethodsWild-type (WT) and 3xTg-AD mice were subjected to UCMS for 8 weeks at 4 months of age, with physiological, vascular, and molecular outcomes assessed at 6 and 9 months of age. We evaluated cerebrovascular function in the middle cerebral artery (MCA) and measured the expression of key mRNA and protein alterations associated with amyloid-β (Aβ) and tau pathology, which drive AD progression.ResultsBoth WT and 3xTg-AD mice exposed to UCMS had significant MCA endothelial dysfunction. Additionally, UCMS accelerated the expression of key AD-related genes, and we observed increased oxidative stress, characterized by higher pro-oxidants and lower antioxidants. Elevated APP and BACE protein levels further suggest that MLS accelerated AD progression.ConclusionsThis study highlights the harmful effects of MLS on cerebrovascular health and the neurobiological mechanisms underlying AD progression. Our findings emphasize the critical link between chronic stress, oxidative dysfunction, and the acceleration of AD progression, offering important insights into potential therapeutic targets for alleviating the impacts of mid-life environmental stressors on AD development.