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Tau分子多样性是造成阿尔茨海默氏病临床异质性的原因
2020-06-23 15:27

2020年6月22日出版的《自然-医学》杂志刊登了美国马萨诸塞州综合医院Bradley T. Hyman小组的最新成果,他们研究发现Tau分子多样性是造成阿尔茨海默氏病(AD)临床异质性的原因。

研究人员假设如果传播的tau蛋白特性在个体之间变化,则tau扩散的动力学也可能会发生变化。研究人员利用生化、生物物理、质谱以及基于细胞和动物的生物活性测定,确定了32例AD患者的tau蛋白特性。

研究发现在可溶性、低聚、种系tau高磷酸化物种中,患者与患者之间存在异质性。Tau定殖活动与该疾病的临床侵袭性相关,某些翻译后修饰(PTM)位点似乎与定殖活动增强和临床效果差有关,而其他则不相关。

这些数据表明,具有“典型” AD的不同个体可能具有不同的tau生化特征。这些数据与以下可能性相关,即与患有癌症的人类似,患有典型表型的AD个体可能具有多种分子驱动因素,这强调了个性化治疗可能减慢AD临床进展的可能。

据介绍,AD引起无法缓和的、进行性认知障碍,但其过程是异质的,认知下降的速度范围广。tau聚集体(神经原纤维缠结)在大脑皮层中的扩散与症状严重程度相关。

附:英文原文

Title: Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease

Author: Simon Dujardin, Caitlin Commins, Aurelien Lathuiliere, Pieter Beerepoot, Analiese R. Fernandes, Tarun V. Kamath, Mark B. De Los Santos, Naomi Klickstein, Diana L. Corjuc, Bianca T. Corjuc, Patrick M. Dooley, Arthur Viode, Derek H. Oakley, Benjamin D. Moore, Kristina Mullin, Dinorah Jean-Gilles, Ryan Clark, Kevin Atchison, Renee Moore, Lori B. Chibnik, Rudolph E. Tanzi, Matthew P. Frosch, Alberto Serrano-Pozo, Fiona Elwood, Judith A. Steen, Matthew E. Kennedy, Bradley T. Hyman

Issue&Volume: 2020-06-22

Abstract: Alzheimer’s disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with ‘typical’ AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.

DOI: 10.1038/s41591-020-0938-9

Source: https://www.nature.com/articles/s41591-020-0938-9

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:87.241
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex


本期文章:《自然—医学》:Online/在线发表

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