Maphis Nicole, Xu Guixiang, Kokiko-Cochran Olga N, Jiang Shanya, Cardona Astrid, Ransohoff Richard M, Lamb Bruce T, Bhaskar Kiran
1 Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque NM 87131, USA.
2 Department of Neurosciences, NC30, 9500 Euclid Avenue, Cleveland Clinic, Cleveland OH 44195, USA.
Brain. 2015 Jun;138(Pt 6):1738-55. doi: 10.1093/brain/awv081. Epub 2015 Mar 31.
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®) 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.
tau蛋白的病理性聚集是阿尔茨海默病及相关tau蛋白病的一个标志。我们之前已经表明，在tau蛋白病的hTau小鼠模型中，小胶质细胞趋化因子受体（CX3CR1）的缺乏导致tau蛋白病理变化加速和记忆障碍。在此，我们表明小胶质细胞以细胞自主方式驱动tau蛋白病理变化。首先，在hTauCx3cr1(-/-)小鼠中，早在2月龄时就出现了tau蛋白过度磷酸化和聚集。其次，CD45(+)小胶质细胞激活与海马体解剖学连接区域的空间记忆缺陷以及tau蛋白病理变化的扩散相关。第三，将源自hTauCx3cr1(-/-)小鼠的纯化小胶质细胞进行过继转移，可在非转基因受体小鼠脑内诱导tau蛋白过度磷酸化。最后，在过继转移接种物中加入白细胞介素1受体拮抗剂（Kineret®）可显著减少小胶质细胞诱导的tau蛋白病理变化。总之，我们的结果表明，反应性小胶质细胞足以驱动tau蛋白病理变化，并与大脑中病理性tau蛋白的扩散相关。
