G-Protein coupled Purinergic P2Y12 receptor interacts and internalizes TauRD-mediated by membrane-associated actin cytoskeleton remodelling in microglia

Abstract

In Alzheimers disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells. Microglial cells are the resident brain macrophage cells that are involved in constant surveillance and are activated by the extracellular deposits. Purinergic receptors are involved in chemotactic migration of microglial cells towards the site of inflammation. In our recent study, we found that microglial P2Y12 receptor has been involved in phagocytosis of full-length Tau species such as monomers, oligomers and aggregates by actin-driven chemotaxis. In this study, we have showed the interaction of repeat-domain of Tau (TauRD) with microglial P2Y12 receptor and analysed the corresponding residues for interaction by various in-silico approaches. In cellular studies, TauRD was found to interact with microglial P2Y12R and induces its cellular expression as confirmed by coimmunoprecipitation and western blot analysis respectively. Similarly, immunofluorescence microscopic studies emphasized that TauRD were phagocytosed by microglial P2Y12R via the membrane-associated actin remodelling as filopodia extension. Furthermore, the P2Yl2R-mediated TauRD internalization has activated the microglia with an increase in the Iba1 level and TauRD become accumulated at peri-nuclear region as localized with Iba1. Altogether, microglial P2Y12R interacts with TauRD and mediates directed migration and activation for its internalization.