慢性创伤性脑病早期病理性Tau构象和磷酸化的特征

N. Kanaan, K. Cox, Victor E. Alvarez, T. Stein, Sharra Poncil, A. Mckee
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引用次数: 86

摘要

慢性创伤性脑病(CTE)是一种神经退行性脑病,发生在重复性头部损伤后。其他tau疾病的一些证据表明,tau寡聚物的形成诱导神经毒性,并且tau寡聚物介导的神经毒性涉及通过暴露tau中的n端基序(磷酸酶激活域(PAD))诱导轴突功能障碍。此外,tau蛋白422丝氨酸磷酸化发生较早,并与阿尔茨海默病(AD)患者的认知能力下降相关。我们对固定脑切片进行免疫组织化学和免疫荧光分析,并对新鲜脑提取物进行生化分析,以表征9-11例CTE患者、非痴呆老年对照和AD (Braak VI)患者大脑中pad暴露的tau (TNT1抗体)、tau寡聚物(TOC1抗体)、S422位点磷酸化的tau (pS422抗体)和D421位点截断的tau (TauC3抗体)的存在。所有3种早期tau标志物(即TNT1, TOC1和pS422)均存在于CTE中,并在血管周围tau病变中显示广泛的共定位,这被认为是CTE的诊断。值得注意的是,在AD中丰富的TauC3表位在CTE中相对较少。总之,这些结果首次描述了PAD暴露、TOC1反应性低聚物、S422磷酸化和CTE tau病理中的TauC3截断。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Characterization of Early Pathological Tau Conformations and Phosphorylation in Chronic Traumatic Encephalopathy
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that develops after repetitive head injury. Several lines of evidence in other tauopathies suggest that tau oligomer formation induces neurotoxicity and that tau oligomer-mediated neurotoxicity involves induction of axonal dysfunction through exposure of an N-terminal motif in tau, the phosphatase-activating domain (PAD). Additionally, phosphorylation at serine 422 in tau occurs early and correlates with cognitive decline in patients with Alzheimer disease (AD). We performed immunohistochemistry and immunofluorescence on fixed brain sections and biochemical analysis of fresh brain extracts to characterize the presence of PAD-exposed tau (TNT1 antibody), tau oligomers (TOC1 antibody), tau phosphorylated at S422 (pS422 antibody), and tau truncated at D421 (TauC3 antibody) in the brains of 9-11 cases with CTE and cases of nondemented aged controls and AD (Braak VI) (n = 6, each). All 3 early tau markers (ie, TNT1, TOC1, and pS422) were present in CTE and displayed extensive colocalization in perivascular tau lesions that are considered diagnostic for CTE. Notably, the TauC3 epitope, which is abundant in AD, was relatively sparse in CTE. Together, these results provide the first description of PAD exposure, TOC1 reactive oligomers, phosphorylation of S422, and TauC3 truncation in the tau pathology of CTE.
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