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CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease.
CSF tau微管结合区鉴定tau缠结和阿尔茨海默病的临床分期。
- 影响因子:7.52
- DOI:10.1093/brain/awaa373
- 作者列表:"Horie K","Barthélemy NR","Sato C","Bateman RJ
- 发表时间:2021-03-03
Abstract
:Tau is a microtubule associated protein in the brain that aggregates in Alzheimer's disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer's disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer's disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer's disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer's disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer's disease and could serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.
摘要
: Tau是大脑中的微管相关蛋白,在阿尔茨海默病中聚集形成病理缠结和神经突。由tau的微管结合区 (MTBR) 组成的不溶性tau聚集体与阿尔茨海默病的认知和临床症状高度相关。相反,在阿尔茨海默病中,可溶性形式的tau (例如CSF总tau和磷酸化tau-181和tau-217) 的水平在tau聚集之前增加,但这些生物标志物不测量tau的MTBR。因此,csfmtbr-tau在阿尔茨海默病中如何改变仍不清楚。在这项研究中,我们使用连续免疫沉淀和化学提取方法,然后通过质谱分析阿尔茨海默病和对照CSF中的MTBR-tau物种。我们定量了CSF中的MTBR-tau特异性区域,并确定含有从残基243开始的区域的物种与tau PET和认知测量高度相关。这一发现表明,含有MTBR上游区域的tau物种的CSF水平可能反映阿尔茨海默病中tau病理学的变化,并可作为阿尔茨海默病分期和跟踪tau导向治疗的发展的生物标志物。
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