美国华盛顿大学医学院的Eric McDade和Randall J. Bateman团队合作发现，可溶的磷酸化tau标记将tau、淀粉样蛋白以及主导遗传的阿尔茨海默症阶段演变联系起来。这一研究成果于2020年3月11日发表在《自然-医学》上。

研究人员在主导遗传的阿尔茨海默症进展研究的四十年中，对脑脊液标记中tau蛋白多个位点的磷酸化状态进行了量化。

他们确定了tau阶段模式，其中特定部位的磷酸化变化发生在疾病进展的不同时期，并随着时间的推移遵循不同的轨迹。

这些tau磷酸化状态的变化与疾病的结构、代谢、神经退行性疾病和临床标志物独特相关。某些伴随着淀粉样β的集聚的tau磷酸化（（p-tau217和p-tau181））状态初始增加要追溯到二十年之前，那时聚集性tau病理学还未发展。其他的（p-tau205和t-tau）随着萎缩和代谢不足而增加，更接近发作症状。

这些发现提供了关于tau、淀粉样β蛋白和神经退行性联系的途径的见解，并可能促进基于tau的治疗的临床试验。

据介绍，研究基于tau的阿尔茨海默症需要了解与tau相关的疾病变化阶段。

附：英文原文

Title: A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

Author: Nicolas R. Barthlemy, Yan Li, Nelly Joseph-Mathurin, Brian A. Gordon, Jason Hassenstab, Tammie. L. S. Benzinger, Virginia Buckles, Anne M. Fagan, Richard J. Perrin, Alison M. Goate, John C. Morris, Celeste M. Karch, Chengjie Xiong, Ricardo Allegri, Patricio Chrem Mendez, Sarah B. Berman, Takeshi Ikeuchi, Hiroshi Mori, Hiroyuki Shimada, Mikio Shoji, Kazushi Suzuki, James Noble, Martin Farlow, Jasmeer Chhatwal, Neill R. Graff-Radford, Stephen Salloway, Peter R. Schofield, Colin L. Masters, Ralph N. Martins, Antoinette OConnor, Nick C. Fox, Johannes Levin, Mathias Jucker, Audrey Gabelle, Sylvain Lehmann, Chihiro Sato, Randall J. Bateman, Eric McDade

Issue&Volume: 2020-03-11

Abstract: Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

DOI: 10.1038/s41591-020-0781-z

Source: https://www.nature.com/articles/s41591-020-0781-z