Psychosocial Stress‐Accelerates Alzheimer’s Disease Progression via the Xanthine Oxidase Pathway

Abstract

AbstractBackgroundVascular contributions to cognitive impairment and dementia are a key pathology associated with Alzheimer’s disease (AD). We have shown that chronic stress induces cerebrovascular dysfunction due to a pro‐oxidative environment, a phenotype similar to that noted with AD. Epidemiological studies also suggest a link between chronic stress and dementia. We tested the hypothesis that chronic stress accelerates the AD pathology via the xanthine oxidase (XO) pathway.MethodsWild type (WT) and Triple transgenic (AD) mice were separated into 1) WT control, 2) WT+UCMS, 3) AD control, 4) AD control+Feb, 5) AD+UCMS, 6) AD+UCMS+Feb. At 4 months‐of‐age, dependent upon group, the unpredicted chronic mild stress (UCMS) model with or without Febuxostat (Feb) treated water (50mg/L) began for 8 weeks. Mice were either euthanized at 6 or 9 months‐of‐age. The middle cerebral artery (MCA) was removed for pressure myography. Brains were homogenized to extract soluble and insoluble fractions of tau proteins using Western blot normalized to GAPDH or B‐actin.ResultsAt 6 months‐of‐age, AD mice displayed a 72% impaired MCA dilation to acetylcholine compared to WT control mice (p<0.05). WT and AD mice that underwent UCMS displayed similar MCA dysfunction compared to AD control mice. UCMS accelerated total and phosphorylated tau protein expression by 83% (p<0.05) and 350% (p<0.001), respectively, compared to AD controls. Treatment with Feb prevented MCA dysfunction in AD control mice, WT UCMS mice, and AD UCMS mice. Feb prevented the increased expression of phosphorylated tau and lowered the total tau protein expression in the AD‐UCMS group. However, total tau protein expression remained higher compared to AD control levels. At 9 months‐of‐age, the majority of these trends persisted with the one exception being a significant impairment in the AD UCMS group compared to both AD control or WT UCMS mice. Tau levels have yet to be processed for 9‐months.ConclusionOverall, these data suggest that chronic stress accelerates cerebrovascular pathology with AD and via a pro‐oxidative state driven by activation of the XO pathway. We will further explore Aβ1‐42 and XO in 3xTg brain homogenates at 6 and 9 months‐of‐age, to better understand how stress accelerates AD pathology.