Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2021 Jan 4;12(1):95. doi: 10.1038/s41467-020-20322-w.
Microtubule-associated protein Tau can form protein aggregates transmissible within the brain, correlating with the progression of tauopathies in humans. The transmission of aggregates requires neuron-released Tau to interact with surface receptors on target cells. However, the underlying molecular mechanisms in astrocytes and downstream effects are unclear. Here, using a spatially resolved proteomic mapping strategy, we show that integrin αV/β1 receptor binds recombinant human Tau, mediating the entry of Tau fibrils in astrocytes. The binding of distinct Tau species to the astrocytic αV/β1 receptor differentially activate integrin signaling. Furthermore, Tau-mediated activation of integrin signaling results in NFκB activation, causing upregulation of pro-inflammatory cytokines and chemokines, induction of a sub-group of neurotoxic astrocytic markers, and release of neurotoxic factors. Our findings suggest that filamentous recombinant human Tau-mediated activation of integrin signaling induces astrocyte conversion towards a neurotoxic state, providing a mechanistic insight into tauopathies.
微管相关蛋白 Tau 可以形成可在大脑内传播的蛋白聚集体，与人类 Tau 病的进展相关。聚集体的传播需要神经元释放的 Tau 与靶细胞表面受体相互作用。然而，星形胶质细胞中的潜在分子机制和下游效应尚不清楚。在这里，我们使用空间分辨蛋白质组学映射策略表明，整合素 αV/β1 受体结合重组人 Tau，介导 Tau 原纤维进入星形胶质细胞。不同 Tau 物种与星形胶质细胞的 αV/β1 受体的结合，差异激活整合素信号。此外，Tau 介导的整合素信号激活导致 NFκB 激活，引起促炎细胞因子和趋化因子的上调，诱导一组神经毒性星形胶质细胞标志物的诱导，并释放神经毒性因子。我们的研究结果表明，丝状重组人 Tau 介导的整合素信号激活诱导星形胶质细胞向神经毒性状态转化，为 Tau 病提供了机制上的见解。
