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

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Burrage, Emily N., Prabhu, Saina, Frazier, James, Simpkins, James, Kelley, Eric E., Chantler, Paul D.
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R2297

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