Chronic Stress exacerbates Tau production in the 3xTg Alzheimer’s Disease Mice

Abstract

Alzheimer’s disease (AD) is the most prevalent type of dementia linked with progressive cognitive decline and behavioral impairment in humans. Currently, an estimated 6.2 million Americans are living with AD, and it is ranked as the 6th leading cause of death in the United States. AD is a multifactorial disorder associated with protein alterations, oxidative stress and neuroinflammation. A cumulative of these factors drive the AD pathogenesis stimulating neurons to produce excessive amounts of β‐amyloid protein (Aβ1‐42) and hyperphosphorylated tau proteins. The complex interplay among the abnormal Aβ1‐42and tau proteins lead to the development of senile plaques and neurofibrillary tangles in the hippocampus of the brain. Chronic psychosocial stress is a risk factor of dementia and is mediated by a pro‐oxidative microenvironment, a fundamental process associated with dementia. We have shown that the xanthine oxidase pathway plays a key role in the chronic stress‐induced cerebrovascular pathology. Thus, we test the hypothesis that chronic stress, using the unpredictable chronic mild stress (UCMS) model, will exacerbate tau pathology and thus, accelerate the early progression of AD. Further, we tested the hypothesis that blocking the xanthine oxidase pathway with febuxostat (Feb) will prevent this accelerated progression of AD.At 4 months‐of‐age, 3xTg mice were separated into 4 groups; AD control, AD control+Feb, AD+UCMS, AD+UCMS+Feb. UCMS was performed for 8 weeks, with or without Feb treated water (50mg/L). Mice were euthanized at 6 months‐of‐age and the harvested brains were flash frozen and stored at ‐80°C. Brains were homogenized to extract soluble and insoluble fractions of tau proteins using Western blot (WB) and normalized to GAPDH or B‐actin.At 6 months‐of‐age, UCMS accelerated total and phosphorylated tau protein expression by 83% (p<0.05) and 350% (p<0.001), respectively, compared to AD controls. Febuxostat prevented the increased expression of phosphorylated tau and lowered the total tau protein expression in the UCMS group. However, total tau protein expression remained higher compared to AD control levels. Thus, overall, these data suggests that chronic stress accelerates tau pathology in 3xTg mice partly through the xanthine oxidase pathway. We will further explore Aβ1‐42and xanthine oxidase in 3xTg brain homogenates at 6 and 9 months‐of‐age, to better understand how stress accelerates AD pathology.