Abstract：
Alzheimer\'s disease, a progressive neurological disorder, is characterized by the accumulation of neurofibrillary tangles and senile plaques by Tau and amyloid-β, respectively, in the brain microenvironment. The misfolded protein aggregates interact with several components of neuronal and glial cells such as membrane lipids, receptors, transporters, enzymes, cytoskeletal proteins, etc. Under pathological conditions, Tau interacts with several G-protein-coupled receptors (GPCRs), which undergoes either receptor signaling or desensitization followed by internalization of the protein complex. The purinergic GPCR, P2Y12 which is expressed in microglial cells, plays a key role in its activation and migration. Microglial cells sense and migrate to the site of injury aided by P2Y12 receptor that interacts with ADP released from damaged cells. P2Y12 receptor also interacts with misfolded Tau accumulated at the extracellular space and promotes receptor-mediated internalization. Immunocolocalization and co-immunoprecipitation studies demonstrated the interaction of Tau species with the P2Y12 receptor. Later, in-silico analyses were carried out with the repeat domain of Tau (TauRD), which has been identified as the interacting partner of P2Y12 receptor by in-vitro studies. Molecular docking and molecular dynamics simulation studies show the stability and the type of interaction in TauRD-receptor complex. Tau interaction with P2Y12 receptor plays a significant role in maintaining the active state of microglia which could lead to neuroinflammation and neuronal damage in AD brain. Hence, blocking P2Y12-Tau interaction and P2Y12-mediated Tau internalization in microglial cells could be possible therapeutic strategies in downregulating the severity of neuroinflammation in AD.
摘要：
老年痴呆症,进行性神经系统疾病,以Tau和β淀粉样蛋白为特征的神经原纤维缠结和老年斑的积累，分别,在大脑微环境中。错误折叠的蛋白质聚集体与神经元和神经胶质细胞的几种成分相互作用，如膜脂，受体,运输商,酶，细胞骨架蛋白,等。在病理条件下,Tau与几种G蛋白偶联受体（GPCRs）相互作用，它经历受体信号传导或脱敏，然后是蛋白质复合物的内化。嘌呤能GPCR，P2Y12在小胶质细胞中表达，在其激活和迁移中起着关键作用。小胶质细胞感知并迁移到由P2Y12受体辅助的损伤部位,所述P2Y12受体与从受损细胞释放的ADP相互作用。P2Y12受体还与在细胞外空间积累的错误折叠Tau相互作用并促进受体介导的内化。免疫定位和共免疫沉淀研究证明了Tau物种与P2Y12受体的相互作用。稍后，使用Tau（TauRD）的重复结构域进行计算机模拟分析，通过体外研究已被确定为P2Y12受体的相互作用伴侣。分子对接和分子动力学模拟研究显示了TauRD-受体复合物的稳定性和相互作用类型。Tau与P2Y12受体的相互作用在维持小胶质细胞的活跃状态中起着重要作用，这可能导致AD脑的神经炎症和神经元损伤。因此，阻断小胶质细胞中P2Y12-Tau相互作用和P2Y12介导的Tau内化可能是下调AD神经炎症严重程度的可能治疗策略.
