Microglia degrade Tau oligomers deposit via purinergic P2Y12-associated podosome and filopodia formation and induce chemotaxis

Cell & Bioscience

Research

Rashmi Das¹  Subashchandrabose Chinnathambi² 

[1] Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, 411008, Pune, India;Academy of Scientific and Innovative Research (AcSIR), 201002, Ghaziabad, India;Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, 411008, Pune, India;Academy of Scientific and Innovative Research (AcSIR), 201002, Ghaziabad, India;Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Institute of National Importance, Hosur Road, 560029, Bangalore, Karnataka, India;

关键词: P2Y12;    Migration;    Filopodia;    Podosome;    Microglia;    Tau oligomers;   

DOI  :  10.1186/s13578-023-01028-0

 received in 2022-10-20, accepted in 2023-04-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundTau protein forms neurofibrillary tangles and becomes deposited in the brain during Alzheimer’s disease (AD). Tau oligomers are the most reactive species, mediating neurotoxic and inflammatory activity. Microglia are the immune cells in the central nervous system, sense the extracellular Tau via various cell surface receptors. Purinergic P2Y12 receptor can directly interact with Tau oligomers and mediates microglial chemotaxis via actin remodeling. The disease-associated microglia are associated with impaired migration and express a reduced level of P2Y12, but elevate the level of reactive oxygen species and pro-inflammatory cytokines.ResultsHere, we studied the formation and organization of various actin microstructures such as-podosome, filopodia and uropod in colocalization with actin nucleator protein Arp2 and scaffold protein TKS5 in Tau-induced microglia by fluorescence microscopy. Further, the relevance of P2Y12 signaling either by activation or blockage was studied in terms of actin structure formations and Tau deposits degradation by N9 microglia. Extracellular Tau oligomers facilitate the microglial migration via Arp2-associated podosome and filopodia formation through the involvement of P2Y12 signaling. Similarly, Tau oligomers induce the TKS5-associated podosome clustering in microglial lamella in a time-dependent manner. Moreover, the P2Y12 was evidenced to localize with F-actin-rich podosome and filopodia during Tau-deposit degradation. The blockage of P2Y12 signaling resulted in decreased microglial migration and Tau-deposit degradation.ConclusionsThe P2Y12 signaling mediate the formation of migratory actin structures like- podosome and filopodia to exhibit chemotaxis and degrade Tau deposit. These beneficial roles of P2Y12 in microglial chemotaxis, actin network remodeling and Tau clearance can be intervened as a therapeutic target in AD.

【 授权许可】

CC BY   
© The Author(s) 2023

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