G-protein coupled receptors regulates Tauopathy in neurodegeneration.

Abstract

In Alzheimer's 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 involved in constant surveillance and activated by the extracellular deposits. Purinergic receptors are involved in the chemotactic migration of microglial cells towards the site of inflammation. From our recent study, we have observed that the microglial P2Y12 receptor is involved in phagocytosis of full-length Tau species such as monomers, oligomers and aggregates by actin-driven chemotaxis. This study shows the interaction of repeat-domain of Tau (Tau^RD) with the microglial P2Y12 receptor and the corresponding residues for interaction have been analyzed by various in-silico approaches. In the cellular studies, Tau^RD was found to interact with microglial P2Y12R and induces its cellular expression confirmed by co-immunoprecipitation and western blot analysis. Furthermore, the P2Y12R-mediated Tau^RD internalization has demonstrated activation of microglia with an increase in the Iba1 level, and Tau^RD becomes accumulated at the peri-nuclear region for the degradation.