【摘要】 目的:研究创伤性脑损伤(traumatic brain injury,TBI)小鼠模型中是否有calpain激活——Dyrk1A(dual specificity tyrosine-phosphorylation-regulated kinase 1A)截断——tau磷酸化和tau病理。方法 :利用表达6种人tau变异体的转基因小鼠(Tg/h Tau)制备轻度到中度的局灶性脑创伤(controlled cortical impact,CCI)模型,用Western Blot和免疫荧光染色研究CCI小鼠海马中calpain的激活、Dyrk1A截断和tau的磷酸化及tau的病理。结果:CCI后30 h小鼠海马中calpain被激活、Dyrk1A截断增加、tau在Thr205和Ser396/404磷酸化水平升高、4R-tau/3R-tau比例增加,在CCI后6周小鼠海马中Dyrk1A的截断没有增加,但在对照侧海马齿状回有异常过度磷酸化tau聚集。结论:局灶性脑创伤导致Tg/h Tau小鼠calpain的急性激活,截断并激活Dyrk1A,促进tau磷酸化和tau病理的发生。更多还原

【Abstract】 Objective: To determine whether traumatic brain injury(TBI)causes the activation of calpain, truncation of dual specificity tyrosine-phosphorylation-regulated kinase 1A(Dyrk1A) and phosphorylation of tau, leading to tau pathology.Methods: We introduced controlled cortical impact(CCI) in adult Tg/h Tau transgenic mice, in which six isoforms of human tau are expressed on a null murine tau background and studied calpain activation,Dyrk1 A truncation and tau phosphorylation with Western Blot and immunofluorescence. Results: We found that calpain was activated, Dyrk1 A was truncated, tau phosphorylation at Thr205 and Ser396/404 was increased and 4R-tau/3R-tau ratio was elevated in the ipsilateral hippocampus of 30 h post CCI. Truncation of Dyrk1 A was not increased in the hippocampi of mice 6 weeks post CCI.However, hyperphosphorylated tau was aggregated in the neuron in the dentat gyrus of contralateral hippocampi, but not in the hippocampi of sham mice detected by immunofluorescent staining with AT8 antibody. Conclusions: The study suggests that CCI causes the activation of calpain, in turn to truncate and activate Dyrk1 A, resulting in tau phosphorylation and imbalanced expression of 3R-tau and 4R-tau, contributing to tau pathogenesis.更多还原