Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model
Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model
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DOI：
10.1016/j.neurobiolaging.2020.01.003
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发表时间：
2020-05-01
影响因子：
4.2
通讯作者：
de Vries, Helga E.
中科院分区：
文献类型：
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作者：
van Olst, Lynn;Verhaege, Daan;de Vries, Helga E.
阿尔茨海默病、进行性核上性麻痹和额颞叶痴呆的特征在于异常tau蛋白的神经元表达、tau过度磷酸化（pTAU）、tau聚集和神经元缠结形成，依次最终导致神经元细胞死亡，这一过程称为tau蛋白病。我们的目的是解决tau蛋白病阶段神经炎症开始，并研究相关的小胶质细胞表型。我们使用Thy 1-hTau.P301S（PS）小鼠，其表达在神经元中特异性具有P301 S突变的人tau。从2个月开始出现显著水平的皮质pTAU。皮质小胶质细胞营养不良的形态复杂性后出现pTAU积累伴随着小胶质细胞溶酶体体积增加和显着的损失的稳态标记Tmem 119。有趣的是，我们检测到PS小胶质细胞溶酶体中神经元pTAU和突触后结构的增加。此外，整体皮质突触后密度下降，在6个月大的PS小鼠。总之，我们的研究结果表明，小胶质细胞采用pTAU相关的表型，并在形态和功能上不同于野生型小胶质细胞后，神经元pTAU积累已经开始。(C)2020年，任作家。爱思唯尔公司出版
Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated. (C) 2020 The Authors. Published by Elsevier Inc.