Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology.
Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology.
复制标题
DOI：
10.3389/fncel.2018.00421
复制
发表时间：
2018
影响因子：
5.3
通讯作者：
Vizuete M
中科院分区：
文献类型：
--
作者：
Romero-Molina C;Navarro V;Sanchez-Varo R;Jimenez S;Fernandez-Valenzuela JJ;Sanchez-Mico MV;Muñoz-Castro C;Gutierrez A;Vitorica J;Vizuete M
小胶质细胞在阿尔茨海默病（AD）等神经退行性疾病的病理过程中起着至关重要的作用。AD中的小胶质细胞反应主要与淀粉样蛋白-β病理学相关，但相对而言，对与tau病理学相关的炎症过程知之甚少。在AD患者的海马中，其中tau病理学比淀粉样蛋白-β病理学更突出，已经报道了小胶质细胞变性过程。在这项工作中，我们直接比较了两种不同的转基因tau小鼠模型：ThyTau 22和P301 S中的小胶质细胞反应。令人惊讶的是，这两种模型在小胶质细胞特征和tau病理学方面显示出重要的差异。在ThyTau 22海马表现出轻度小胶质细胞活化的情况下，P301 S小鼠表现出与高磷酸化tau积累平行的强小胶质细胞应答。这种差异磷酸化tau表达可以解释这两种tau菌株中不同的小胶质细胞反应。然而，来自ThyTau 22海马的可溶性（S1）组分呈现相对高含量的可溶性磷酸化tau（AT 8阳性），并且在体外对小胶质细胞具有高毒性，而来自P301 S小鼠的相应S1组分显示低可溶性磷酸化tau水平，并且对小胶质细胞没有毒性。因此，不仅磷酸化tau的表达水平，而且磷酸化tau的聚集在两种模型之间应该不同。事实上，P301 S小鼠中的大多数tau形式是聚集的，因此形成不溶性tau种类。我们得出结论，不同的因素，如tau突变，积累，磷酸化，和/或聚集可以解释在这两个tau模型中观察到的不同的小胶质细胞反应。出于这个原因，破译小胶质细胞的毒性tau种类的分子性质可能是一种有前途的治疗方法，以恢复在AD海马中观察到的免疫保护缺陷。
Microglial cells are crucial players in the pathological process of neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglial response in AD has been principally studied in relation to amyloid-beta pathology but, comparatively, little is known about inflammatory processes associated to tau pathology. In the hippocampus of AD patients, where tau pathology is more prominent than amyloid-beta pathology, a microglial degenerative process has been reported. In this work, we have directly compared the microglial response in two different transgenic tau mouse models: ThyTau22 and P301S. Surprisingly, these two models showed important differences in the microglial profile and tau pathology. Where ThyTau22 hippocampus manifested mild microglial activation, P301S mice exhibited a strong microglial response in parallel with high phospho-tau accumulation. This differential phospho-tau expression could account for the different microglial response in these two tau strains. However, soluble (S1) fractions from ThyTau22 hippocampus presented relatively high content of soluble phospho-tau (AT8-positive) and were highly toxic for microglial cells in vitro, whereas the correspondent S1 fractions from P301S mice displayed low soluble phospho-tau levels and were not toxic for microglial cells. Therefore, not only the expression levels but the aggregation of phospho-tau should differ between both models. In fact, most of tau forms in the P301S mice were aggregated and, in consequence, forming insoluble tau species. We conclude that different factors as tau mutations, accumulation, phosphorylation, and/or aggregation could account for the distinct microglial responses observed in these two tau models. For this reason, deciphering the molecular nature of toxic tau species for microglial cells might be a promising therapeutic approach in order to restore the deficient immunological protection observed in AD hippocampus.
登录
查看更多内容
耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。
影响因子：
8.8
作者：
Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
通讯作者：
Gomez-Nicola D
影响因子：
4
作者：
Gutierrez, Antonia;Vitorica, Javier
通讯作者：
Vitorica, Javier
影响因子：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier
影响因子：
4.4
作者：
Kovac, Andrej;Zilka, Norbert;Novak, Michal
通讯作者：
Novak, Michal
影响因子：
8.6
作者：
Henkel, K;Karitzky, J;Landwehrmeyer, GB
通讯作者：
Landwehrmeyer, GB