Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes
Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes
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DOI：
10.1038/s41598-019-41105-4
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发表时间：
2019-03-15
影响因子：
4.6
通讯作者：
Pedersen, Jan Torleif
中科院分区：
文献类型：
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作者：
Andersson, Christian Rungsted;Falsig, Jeppe;Pedersen, Jan Torleif
神经退行性疾病如阿尔茨海默病的特征在于脑中过度磷酸化的tau蛋白的进行性扩散和积累。已显示抗tau抗体在体内模型中减少tau病理学，并且已提出抗体介导的由小胶质细胞发挥的tau清除是一个促成因素。通过将体外培养的原代小胶质细胞置于与病理性tau复合的抗磷酸化tau抗体中，我们表明小胶质细胞以依赖于Fc γ R相互作用和功能性溶酶体的方式内化和降解tau。最近已经讨论了诱导tau清除是否需要抗tau抗体效应子功能。使用具有受损的Fc γ R结合的抗体和未受损的对照抗体，我们表明诱导tau的小胶质细胞清除需要抗体效应子功能。了解使用治疗性抗体靶向小胶质细胞的炎症后果在开发这些分子用于临床用途时很重要。使用RNA测序，我们表明用抗tau抗体处理增加了编码促炎标志物的mRNA的转录，但是抗体处理的细胞的mRNA表达谱与LPS激活的小胶质细胞的谱不同。我们进一步证明，单独的小胶质细胞活化不足以诱导显著的tau蛋白清除。
Neurodegenerative diseases such as Alzheimer's disease are characterized by the progressive spreading and accumulation of hyper-phosphorylated tau protein in the brain. Anti-tau antibodies have been shown to reduce tau pathology in in vivo models and antibody-mediated clearance of tau exerted by microglia has been proposed as a contributing factor. By subjecting primary microglia cultured in vitro to anti-phospho-tau antibodies in complex with pathological tau, we show that microglia internalise and degrade tau in a manner that is dependent on Fc gamma R interaction and functional lysosomes. It has recently been discussed if anti-tau antibody effector-functions are required for induction of tau clearance. Using antibodies with compromised Fc gamma R binding and non-compromised control antibodies we show that antibody effector functions are required for induction of microglial clearance of tau. Understanding the inflammatory consequences of targeting microglia using therapeutic antibodies is important when developing these molecules for clinical use. Using RNA sequencing, we show that treatment with anti-tau antibodies increases transcription of mRNA encoding pro-inflammatory markers, but that the mRNA expression profile of antibody-treated cells differ from the profile of LPS activated microglia. We further demonstrate that microglia activation alone is not sufficient to induce significant tau clearance.