02674nas a2200229   4500008004100000245012800041210006900169260000800238300000800246490000700254520187200261653002402133653002002157653001602177653001402193653001102207653000802218100003402226700001602260700003602276856013202312       2020                        eng d00aInteraction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation0 aInteraction of Tau with the chemokine receptor CX3CR1 and its ef  cSEP  a1090 v103 a<p>Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive loss of memory and dementia. The pathological hallmarks of AD include extracellular accumulation of amyloid-beta peptides forming senile plaques and intracellular accumulation of Tau oligomers and filamentous species. Tau is a microtubule-binding protein that stabilizes tubulin to form microtubules under physiological condition. In AD/ pathological condition, Tau detaches from microtubules and aggregates to form oligomers of different sizes and filamentous species such as paired helical filaments. Microglia are the resident brain macrophages that are involved in the phagocytosis of microbes, cellular debris, misfolded and aggregated proteins. Chemokine receptor, CX3CR1 is mostly expressed on microglia and is involved in maintaining the microglia in a quiescent state by binding to its ligand, fractalkine (CX3CL1), which is expressed in neurons as both soluble or membrane-bound state. Hence, under physiological conditions, the CX3CR1/CX3CL1 axis plays a significant role in maintaining the central nervous system (CNS) homeostasis. Further, CX3CR1/CX3CL1 signalling is involved in the synthesis of anti-inflammatory cytokines and also has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation. In AD brain, the expression level of fractalkine is reduced, and hence Tau competes to interact with its receptor, CX3CR1. In microglia, phagocytosis and internalization of extracellular Tau species occurs in the presence of a chemokine receptor, CX3CR1 which binds directly to Tau and promotes its internalization. In this review, the pathophysiological roles of CX3CR1/fractalkine signalling in microglia and neurons at different stages of Alzheimer's disease and the possible role of CX3CR1/Tau signalling has been widely discussed.</p>
10aAlzheimer's disease10aCX3CR1 receptor10aFractalkine10amicroglia10aNeuron10aTau1 aChidambaram, Hariharakrishnan1 aDas, Rashmi1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/interaction-tau-chemokine-receptor-cx3cr1-and-its-effect-microglial-activation-migration-and02456nas a2200241   4500008004100000022001400041245015600055210006900211260000800280300001100288490000800299520165300307653002601960653002001986653001402006653001102020653001702031653000802048100003402056700001602090700003602106856007202142       2022                        eng d  a0171-933500aG-protein coupled purinergic P2Y12 receptor interacts and internalizes TauRD-mediated by membrane-associated actin cytoskeleton remodeling in microglia0 aGprotein coupled purinergic P2Y12 receptor interacts and interna  cAPR  a1512010 v1013 aIn 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 (TauRD) with the microglial P2Y12 receptor and the corresponding residues for interaction have been analysed by various in-silico approaches. In the cellular studies, TauRD was found to interact with microglial P2Y12R and induces its cellular expression confirmed by co-immunoprecipitation and western blot analysis. Furthermore, the P2Y12R-mediated TauRD internalization has demonstrated activation of microglia with an increase in the Iba1 level, and TauRD becomes accumulated at the peri-nuclear region for the degradation. Similarly, immunofluorescence microscopic studies emphasized that TauRD is phagocytosed by microglial P2Y12R via the membrane-associated actin remodeling as filopodia extension. Upon internalization, we have demonstrated the P2Y12R signaling-mediated degradation of accumulated TauRD by lysosomal pathway. Altogether, microglial P2Y12R interacts with TauRD and mediates directed migration and activation for its internalization and degradation.10aAlzheimer’s disease10aInternalization10amicroglia10aP2Y12R10aPhagocytosis10aTau1 aChidambaram, Hariharakrishnan1 aDas, Rashmi1 aChinnathambi, Subashchandrabose  uhttps://www.sciencedirect.com/science/article/pii/S0171933522000048