Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, 28041, Madrid, Spain.
Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Universidad Autónoma de Madrid, C/ Nicolás Cabrera 1, 28049, Madrid, Spain.
Mol Neurodegener. 2017 Aug 15;12(1):59. doi: 10.1186/s13024-017-0200-1.
Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism.
We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1 mice). The expression of CX3CR1, CX3CL1 and the microglial phagocytic phenotype were studied in brain tissue samples from AD patients.
Tau binding to CX3CR1 triggers the internalization of the former by microglia, whereas S396 Tau phosphorylation decreases the binding affinity of this protein to CX3CR1. Of note, the progressive increase in the levels of phosho-Tau occurred in parallel with an increase in CX3CR1. In addition, our studies suggest that the phagocytic capacity of microglia in brain tissue samples from AD patients is decreased. Furthermore, the CX3CR1/CX3CL1 axis may be impaired in late stages of the disease.
Our data suggest that the CX3CR1/CX3CL1 axis plays a key role in the phagocytosis of Tau by microglia in vitro and in vivo and that it is affected as AD progresses. Taken together, our results reveal CX3CR1 as a novel target for the clearance of extracellular Tau.
细胞外 Tau 对邻近细胞有毒性，并且促进 AD 的进展。CX3CL1/CX3CR1 轴是神经元/小胶质细胞通讯的重要机制。
我们研究了小胶质细胞对 Tau 的清除作用，包括体外（用 Cy5-Tau 处理小胶质细胞原代培养物、亲和层析研究 Tau 与 CX3CR1 的结合、以及 Tau-CX3CL1 竞争实验）和体内（WT 和 CX3CR1 小鼠立体定位注射 Cy5-Tau）。研究了 AD 患者脑组织样本中 CX3CR1、CX3CL1 的表达和小胶质细胞吞噬表型。
Tau 与 CX3CR1 结合触发小胶质细胞内化前者，而 S396 Tau 磷酸化降低了该蛋白与 CX3CR1 的结合亲和力。值得注意的是，磷酸化 Tau 水平的逐渐增加与 CX3CR1 的增加平行发生。此外，我们的研究表明 AD 患者脑组织样本中小胶质细胞的吞噬能力下降。此外，CX3CR1/CX3CL1 轴可能在疾病的晚期受损。
我们的数据表明，CX3CR1/CX3CL1 轴在体外和体内小胶质细胞对 Tau 的吞噬作用中起关键作用，并且随着 AD 的进展而受到影响。总之，我们的结果揭示了 CX3CR1 作为清除细胞外 Tau 的新靶点。
