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.

中文翻译：

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在神经元特异性 P301S tau 蛋白病变小鼠模型中，磷酸化 tau 蛋白聚集后出现小胶质细胞激活。

阿尔茨海默病、进行性核上性麻痹和额颞叶痴呆的特征是异常 tau 蛋白的神经元表达、tau 过度磷酸化 (pTAU)、tau 聚集和神经原纤维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。我们的目标是解决 tau 蛋白病变阶段神经炎症开始的问题，并研究相关的小胶质细胞表型。我们使用 Thy1-hTau.P301S (PS) 小鼠表达人类 tau，特别是在神经元中具有 P301S 突变。从 2 个月起就存在显着水平的皮质 pTAU。皮质小胶质细胞营养不良的形态复杂性在 pTAU 积累后出现，伴随着小胶质细胞溶酶体体积的增加和稳态标记 Tmem119 的显着丧失。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，6 个月大的 PS 小鼠的整体皮质突触后密度降低。总之，我们的结果表明小胶质细胞采用 pTAU 相关表型，并且在神经元 pTAU 积累开始后在形态和功能上与野生型小胶质细胞不同。