02674nas a2200229 4500008004100000022001400041245007900055210006900134260000900203300001200212490000800224520191600232653002402148653001002172653001402182653002402196653002402220653002002244100003402264700003602298856011002334 2020 eng d a0306-452200aG-protein coupled receptors and tau-different roles in alzheimer's disease0 aGprotein coupled receptors and taudifferent roles in alzheimers  cJUL  a198-2140 v4383 a

Post-translational modification of Tau, a microtubule-associated protein in the neuronal cell, plays a major role in Alzheimer's disease. Tau is an axonal protein expressed in mature neurons that promote the self-assembly of tubulin into microtubules and its stabilization in neurons. Phosphorylation of Tau makes it prone to aggregation at the intra-neuronal region leading to impaired neurotransmission and dementia. Tau aggregates undergo trans-cellular propagation by the release of fibrillar species into the extra-cellular environment from damaged and infected neurons that can be internalized by neighbouring neuronal and glia cells and promotes aggregation in healthy cells. G-protein coupled receptors, the largest group of seven transmembrane receptors, are involved in neuronal signal transduction in response to various signals such as hormones and neurotransmitters. In Alzheimer's disease, GPCRs are involved in phosphorylation of Tau through various downstream kinases such as GSK-3b, CDK-5 and ERKs signalling cascade. Several neuronal GPCRs that are involved in Tau phosphorylation are elaborated in this review. The astrocytic GPCR, Tau phosphorylation mediated by CaS receptors and its propagation by exosomes are also elaborated. In the microglia, the extra-cellular Tau binding to a chemokine GPCR, CX3CR1 triggers its internalization, whereas Tau phosphorylation at specific sites decreases its binding affinity to this receptor. Here we highlight the role of GPCRs in Tau phosphorylation and Tau interaction in different cells of the nervous system. Hence, the role of GPCRs are attaining more attention in the therapeutic field of Alzheimer's disease. Specific agonists/antagonists and allosteric modulators could be the potential target for therapy against GPCR-mediated Tau phosphorylation in Alzheimer's disease. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

10aAlzheimer's disease10aGPCRs10amicroglia10aTau internalization10aTau phosphorylation10aTau propagation1 aChidambaram, Hariharakrishnan1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/g-protein-coupled-receptors-and-tau-different-roles-alzheimers-disease02674nas 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

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.

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-and02238nas a2200217 4500008004100000022001400041245008900055210006900144260000800213520145500221653002401676653002501700653001601725653001401741653002901755100002501784700003401809700002701843700003601870856011401906 2020 eng d a0272-434000aRole of microglia in regulating cholesterol and tau pathology in alzheimer's disease0 aRole of microglia in regulating cholesterol and tau pathology in cMAY3 a

Cholesterol, a principal constituent of the cell membrane, plays a crucial role in the brain by regulating the synaptic transmission, neuronal signaling, as well as neurodegenerative diseases. Defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-beta protein. Tau, a major microtubule-associated protein in the brain, is the key regulator of the mature neuron. Abnormally hyperphosphorylated Tau hampers the major functions related to microtubule assembly by promoting neurofibrillary tangles of paired helical filaments, twisted ribbons, and straight filaments. The observed pathological changes due to impaired cholesterol and Tau protein accumulation cause Alzheimer's disease. Thus, in order to regulate the pathogenesis of Alzheimer's disease, regulation of cholesterol metabolism, as well as Tau phosphorylation, is essential. The current review provides an overview of (1) cholesterol synthesis in the brain, neurons, astrocytes, and microglia; (2) the mechanism involved in modulating cholesterol concentration between the astrocytes and brain; (3) major mechanisms involved in the hyperphosphorylation of Tau and amyloid-beta protein; and (4) microglial involvement in its regulation. Thus, the answering key questions will provide an in-depth information on microglia involvement in managing the pathogenesis of cholesterol-modulated hyperphosphorylated Tau protein.

10aAlzheimer's disease10aAmyloid-beta protein10aCholesterol10amicroglia10aTau hyperphosphorylation1 aNanjundaiah, Shwetha1 aChidambaram, Hariharakrishnan1 aChandrashekar, Madhura1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/role-microglia-regulating-cholesterol-and-tau-pathology-alzheimers-disease02539nas a2200241 4500008004100000022001400041245015800055210006900213260000800282300001100290490000800301520167700309653002401986653002002010653001402030653001102044653001702055653001202072100003402084700001602118700003602134856012702170 2022 eng d a0171-933500aG-protein coupled purinergic P2Y12 receptor interacts and internalizes Tau(RD)-mediated by membrane-associated actin cytoskeleton remodeling in microglia0 aGprotein coupled purinergic P2Y12 receptor interacts and interna cAPR a1512010 v1013 a

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 analysed 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. Similarly, immunofluorescence microscopic studies emphasized that Tau(RD) 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 Tau(RD) by lysosomal pathway. Altogether, microglial P2Y12R interacts with Tau(RD) and mediates directed migration and activation for its internalization and degradation.

10aAlzheimer's disease10aInternalization10amicroglia10aP2Y12R10aPhagocytosis10aTau(RD)1 aChidambaram, Hariharakrishnan1 aDas, Rashmi1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/g-protein-coupled-purinergic-p2y12-receptor-interacts-and-internalizes-taurd-mediated-0