Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Institute of National Importance, Hosur Road, Bangalore 560029, Karnataka, India.
Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Biochim Biophys Acta Mol Cell Res. 2023 Jun;1870(5):119477. doi: 10.1016/j.bbamcr.2023.119477. Epub 2023 Apr 13.
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is associated with protein misfolding, plaque accumulation, neuronal dysfunction, synaptic loss, and cognitive decline. The pathological cascade of AD includes the intracellular Tau hyperphosphorylation and its subsequent aggregation, extracellular Amyloid-β plaque formation and microglia-mediated neuroinflammation. The extracellular release of aggregated Tau is sensed by surveilling microglia through the involvement of various cell surface receptors. Among all, purinergic P2Y12R signaling is involved in microglial chemotaxis towards the damaged neurons. Microglial migration is highly linked with membrane-associated actin remodeling leading to the phagocytosis of extracellular Tau species. Here, we studied the formation of various actin structures such as podosome, lamellipodia and filopodia, in response to extracellular Tau monomers and aggregates. Microglial podosomes are colocalized with actin nucleator protein WASP, Arp2 and TKS5 adaptor protein during Tau-mediated migration. Moreover, the P2Y12 receptors were associated with F-actin-rich podosome structures, which signify the potential of Tau aggregates in microglial chemotaxis through the involvement of actin remodeling.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，与蛋白质错误折叠、斑块积累、神经元功能障碍、突触丧失和认知能力下降有关。AD 的病理级联反应包括细胞内 Tau 过度磷酸化及其随后的聚集、细胞外 Amyloid-β 斑块形成以及小胶质细胞介导的神经炎症。聚集的 Tau 通过各种细胞表面受体的参与被监测小胶质细胞感知到细胞外释放。在所有这些受体中，嘌呤能 P2Y12R 信号参与小胶质细胞向受损神经元的趋化运动。小胶质细胞的迁移与膜相关的肌动蛋白重塑高度相关，导致细胞外 Tau 物种的吞噬。在这里，我们研究了各种肌动蛋白结构的形成，如足突、片状伪足和丝状伪足，以响应细胞外 Tau 单体和聚集体。在 Tau 介导的迁移过程中，小胶质细胞的足突与肌动蛋白成核蛋白 WASP、Arp2 和 TKS5 衔接蛋白共定位。此外，P2Y12 受体与富含 F-肌动蛋白的足突结构相关，这表明 Tau 聚集物通过肌动蛋白重塑参与小胶质细胞趋化运动的潜力。
