Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
Neurobiol Aging. 2022 Jan;109:52-63. doi: 10.1016/j.neurobiolaging.2021.09.006. Epub 2021 Sep 20.
Pathological aggregation of tau and neuroinflammatory changes mark the clinical course of Alzheimer's disease and related tauopathies. To understand the correlation between these pathological hallmarks and functional deficits, we assessed behavioral and physiological deficits in the PS19 mouse model, a broadly utilized model of tauopathy. At 9 months, PS19 mice have characteristic hyperactive behavior, a decline in motor strength, and deterioration in physiological conditions marked by lower body temperature, reduced body weight, and an increase in measures of frailty. Correlation of these deficits with different pathological hallmarks revealed that pathological tau species, characterized by soluble p-tau species, and tau seeding bioactivity correlated with impairment in grip strength and thermal regulation. On the other hand, astrocyte reactivity showed a positive correlation with the hyperactive behavior of the PS19 mice. These results suggest that a diverse spectrum of soluble pathological tau species could be responsible for different symptoms and that neuroinflammation could contribute to functional deficits independently from tau pathology. These observations enhance the necessity of a multi-targeted approach for the treatment of neurodegenerative tauopathies.
tau 蛋白病理性聚集和神经炎症变化标志着阿尔茨海默病及相关 tau 病的临床进程。为了理解这些病理特征与功能缺陷之间的相关性，我们评估了 PS19 小鼠模型（一种广泛应用的 tau 病模型）的行为和生理缺陷。在 9 个月时，PS19 小鼠表现出特征性的过度活跃行为、运动力量下降以及生理状况恶化，表现为体温降低、体重减轻和脆弱性增加。这些缺陷与不同病理特征的相关性表明，可溶性 p-tau 物种和 tau 种子生物活性等病理性 tau 物种与握力和体温调节受损相关。另一方面，星形胶质细胞反应与 PS19 小鼠的过度活跃行为呈正相关。这些结果表明，不同的可溶性病理性 tau 物种可能导致不同的症状，神经炎症可能独立于 tau 病理学导致功能缺陷。这些观察结果增强了针对神经退行性 tau 病采用多靶点治疗方法的必要性。
