Chronic Stress Accelerates the Progression of Cerebrovascular Dysfunction with Alzheimer's Disease.

Vascular contributions to cognitive impairment and dementia are a key pathology associated with Alzheimer's disease (AD). Past work in our lab has shown that chronic stress induces cerebrovascular dysfunction due to a pro-oxidative environment while epidemiological studies suggest a link between chronic stress and dementia. With this in mind, we tested the hypothesis that chronic stress accelerates the vascular pathology associated with AD potentially via the xanthine oxidase pathway. Here, we utilized a triple transgenic mouse model of AD (3xTg AD) combined with our unpredicted chronic mild stress paradigm (UCMS) and a xanthine oxidase inhibitor, Febuxostat, to examine middle cerebral artery (MCA) function. Beginning at 4 months of age all mice underwent the UCMS paradigm for 8 weeks total while a subset of mice were given Febuxostat treated water (50mg/L). Mice were either euthanized immediately following the 8 weeks of UCMS (at 6 months-of-age) or euthanized 3 months post-UCMS (at 9 months-of-age). Following euthanasia, the MCA's were removed and positioned in a pressurized myobath. The MCA was exposed to increasing concentrations of acetylcholine (ACh; 10-9M to 10-4M), phenylephrine (PE; 10-9M to 10-4M), and sodium nitroprusside (SNP; 10-9M to 10-4M). At 6 months-of-age, AD mice displayed impaired MCA dilation to ACh compared to WT control mice (8.2±1.4mm to 17.5±2.1mm, respectively; p<0.05). WT and AD mice that underwent UCMS displayed similar response to ACh compared to AD control mice (8.25±0.3mm and 7.125±1mm to 8.2±1.4mm, respectively). Treatment with Febuxostat prevented MCA dysfunction in AD control mice, WT UCMS mice, and AD UCMS mice (8.2±1.4mm vs 17.1±1mm, 8.25±0.3mm vs 18.25±1.1mm, 7.1±1mm vs 17.2±0.9mm, respectively; p<0.05). No differences were found between groups in the PE or SNP response. Interestingly, at 9 months-of-age, the majority of these trends persisted with the one exception being a compounded impairment in the AD UCMS group compared to both AD control or WT UCMS mice (3.5±1.2mm vs 8.5±1mm, and 9.3±2.2mm, respectively; p<0.05). Overall, these data suggest that chronic stress does accelerate the cerebrovascular pathology associated with AD and potentially via a pro-oxidative state driven by activation of the xanthine oxidase pathway.