Chronic Social and Psychological Stress Impact Select Neuropathologies in the PS19 Mouse Model of Tauopathy

Objective: Despite advances toward understanding the etiology of Alzheimer's disease (AD), it remains unclear which aspects of this disease are affected by environmental factors. Chronic life stress increases the risk of aging-related diseases including AD. The impact of stress on tauopathies remains understudied. We examined the effects of stress elicited by social (chronic subordination stress [CSS]) or psychological/physical (chronic restraint stress [CRS]) factors on the PS19 mouse model of tauopathy. Methods: Male PS19 mice (average age, 6.3 months) were randomized to receive CSS or CRS, or to remain as singly housed controls. Behavioral tests were used to assess anxiety-like behaviors and cognitive functions. Immunofluorescence staining and Western blotting analysis were used to measure levels of astrogliosis, microgliosis, and tau burden. Immunohistochemistry was used to assess glucocorticoid receptor expression. Results: PS19 mice exhibit neuroinflammation (glial fibrillary acidic protein, t tests: p = .0297; allograft inflammatory factor 1, t tests: p = .006) and tau hyperphosphorylation (t test, p = .0446) in the hippocampus, reduced anxiety (post hoc, p = .046), and cognitive deficits, when compared with wild-type mice. Surprisingly, CRS reduced hippocampal levels of both total tau and phospho-tauS404 (t test, p = .0116), and attenuated some aspects of both astrogliosis and microgliosis in PS19 mice (t tests, p = .068-.0003); however, this was not associated with significant changes in neurodegeneration or cognitive function. Anxiety-like behaviors were increased by CRS (post hoc, p = .046). Conversely, CSS impaired spatial learning in Barnes maze without impacting tau phosphorylation or neurodegeneration and having a minimal impact on gliosis. Conclusions: Our results demonstrate that social or psychological stress can differentially impact anxiety-like behavior, select cognitive functions, and some aspects of tau-dependent pathology in PS19 male mice, providing entry points for the development of experimental approaches designed to slow AD progression.