From the Department of Integrative Biology and Physiology (Lyons, Razzoli, Mansk, McGonigle, Sabarinathan, Bartolomucci) and Graduate Program in Neuroscience (Lyons), University of Minnesota, Minneapolis, Minnesota; Departments of Biochemistry and Molecular Biology (Graves, Jeganathan, van Deursen, Baker) and Pediatric and Adolescent Medicine (Graves, Jeganathan, van Deursen, Baker), Mayo Clinic; Paul F. Glenn Center for the Biology of Aging at Mayo Clinic (Baker), Rochester, Minnesota; and Department of Medicine and Surgery (Bartolomucci), University of Parma, Parma, Italy.
Psychosom Med. 2024 Jun 1;86(5):366-378. doi: 10.1097/PSY.0000000000001256. Epub 2023 Oct 3.
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.
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.
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-tau S404 ( 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.
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.
尽管人们在理解阿尔茨海默病（AD）的病因方面取得了进展，但仍不清楚哪些方面受到环境因素的影响。慢性生活压力会增加与衰老相关的疾病（包括 AD）的风险。压力对 tau 病的影响仍研究不足。我们研究了社会（慢性从属压力[CSS]）或心理/生理（慢性约束压力[CRS]）因素引起的压力对 tau 病 PS19 小鼠模型的影响。
雄性 PS19 小鼠（平均年龄 6.3 个月）随机分为接受 CSS 或 CRS，或保持单独饲养对照。行为测试用于评估焦虑样行为和认知功能。免疫荧光染色和 Western blot 分析用于测量星形胶质细胞增生、小胶质细胞增生和 tau 负荷水平。免疫组织化学用于评估糖皮质激素受体表达。
与野生型小鼠相比，PS19 小鼠在海马体中表现出神经炎症（胶质纤维酸性蛋白，t 检验：p =.0297；同种异体炎症因子 1，t 检验：p =.006）和 tau 过度磷酸化（t 检验，p =.0446），焦虑减少（事后，p =.046），认知功能障碍。令人惊讶的是，CRS 降低了 PS19 小鼠海马体中总 tau 和磷酸化 tau S404 的水平（t 检验，p =.0116），并减轻了星形胶质细胞增生和小胶质细胞增生的某些方面（t 检验，p =.068-0.0003）；然而，这与神经退行性变或认知功能的显著变化无关。CRS 增加了焦虑样行为（事后，p =.046）。相反，CSS 损害了 Barnes 迷宫中的空间学习，而不影响 tau 磷酸化或神经退行性变，对神经胶质增生的影响最小。
我们的结果表明，社会或心理压力可以以不同的方式影响焦虑样行为、某些认知功能和 PS19 雄性小鼠的 tau 依赖性病理学的某些方面，为开发旨在减缓 AD 进展的实验方法提供了切入点。
