小柯机器人

美国华盛顿大学医学院David M. Holtzman团队近期取得重要工作进展，他们研究发现小胶质细胞介导的T细胞浸润驱动tau蛋白病的神经退行性病变。相关研究成果2023年3月8日在线发表于《自然》杂志上。

据介绍，β淀粉样蛋白在细胞外沉积为神经炎斑块，以及过度磷酸化聚集的 tau 细胞在细胞内积累为神经原纤维缠结，这是阿尔茨海默病的两个特征性标志。阿尔茨海默病脑萎缩的区域进展与tau积聚高度相关，但与淀粉样蛋白沉积无关，tau介导的神经变性机制仍不清楚。先天性免疫反应是一些神经退行性疾病发生和发展的共同途径。到目前为止，在β淀粉样蛋白或tau病理的存在下，对适应性免疫反应的程度或作用及其与先天免疫反应的相互作用知之甚少。

研究人员系统地比较了淀粉样蛋白沉积或tau聚集和神经退行性病变小鼠大脑中的免疫环境。研究人员发现，患有tau病的小鼠而不是淀粉样蛋白沉积的小鼠产生了独特的先天性和适应性免疫反应，小胶质细胞或T细胞的耗竭阻断了tau介导的神经变性。在患有tau病的小鼠和阿尔茨海默病的大脑中，tau病理区的T细胞数量，特别是细胞毒性T细胞数量显著增加。T细胞数量与神经元损失的程度相关，并且细胞动态地将其细胞特征从激活状态转变为耗尽状态，并伴随着独特的TCR克隆扩增。γ干扰素和PDCD1信号的抑制都能显著改善脑萎缩。

因此，这一研究结果揭示了一种涉及激活的小胶质细胞和T细胞反应的与tau病和神经变性相关免疫中枢，它可以作为预防阿尔茨海默病和原发性神经变性的治疗靶点。

附：英文原文

Title: Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy

Author: Chen, Xiaoying, Firulyova, Maria, Manis, Melissa, Herz, Jasmin, Smirnov, Igor, Aladyeva, Ekaterina, Wang, Chanung, Bao, Xin, Finn, Mary Beth, Hu, Hao, Shchukina, Irina, Kim, Min Woo, Yuede, Carla M., Kipnis, Jonathan, Artyomov, Maxim N., Ulrich, Jason D., Holtzman, David M.

Issue&Volume: 2023-03-08

Abstract: Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease1,2. The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition3,4,5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies.

DOI: 10.1038/s41586-023-05788-0

Source: https://www.nature.com/articles/s41586-023-05788-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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