Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain
Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain
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DOI：
10.1093/brain/awv081
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发表时间：
2015-06-01
期刊：
影响因子：
14.5
通讯作者：
Bhaskar, Kiran
中科院分区：
文献类型：
--
作者：
Maphis, Nicole;Xu, Guixiang;Bhaskar, Kiran
Tau的病理性聚集是阿尔茨海默病和相关tauopathy的一个特征。我们之前已经证明，小胶质细胞分裂因子受体(CX3CR1)的缺失导致了tau病理的加速和记忆障碍。在这里，我们展示了小胶质细胞以细胞自主的方式驱动tau病理。首先，tau的过度磷酸化和聚集早在2个月龄的hTauCx3cr1(-/-)小鼠中就发生了。其次，CD45(+)小胶质细胞的激活与空间记忆缺陷和tau病理在解剖连接的海马区的扩散有关。第三，过继转移来自hTauCx3cr1(-/-)小鼠的纯化小胶质细胞诱导了非转基因受体小鼠脑内tau的过度磷酸化。最后，在过继转移接种中加入白细胞介素1受体拮抗剂(Kineet(R))大大减少了小胶质细胞诱导的tau病理。综上所述，我们的结果表明，反应性小胶质细胞足以驱动tau病理，并与病理性tau在脑内的扩散相关。
Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret (R)) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.