03275nas a2200229   4500008004100000022001400041245010600055210006900161260000900230300001200239490000800251520249700259653002102756653002402777653001402801653001802815653002102833653001402854100001602868700003602884856012502920       2020                        eng d  a0306-452200aActin-mediated microglial chemotaxis via G-protein coupled purinergic receptor in alzheimer's disease0 aActinmediated microglial chemotaxis via Gprotein coupled puriner  cNOV   a325-3360 v4483 a<p>Alzheimer's disease (AD) is a neurodegenerative disease mainly associated with aging, oxidative stress and genetic mutations. There are two pathological proteins involved in AD; Amyloid-beta peptide and microtubule-associated protein Tau (MAPT). The beta- and gamma-secretase enzyme cleaves the Amyloid precursor protein, which results in the formation of extracellular plaques in brain. While, Tau undergoes hyperphosphorylation and other post-translational modifications (PTMs), which eventually generates Tau oligomers, and intracellular neurofibrillary tangles (NFTs) in neurons. Moreover, the brain-resident glia and infiltrated macrophages elevate the level of CNS inflammation, which trigger the oxidative damage of neuronal circuits by reactive oxygen species (ROS) and Nitric oxide (NO). Microglia is the primary immune cell in the CNS, which is continuously surveilling the neuronal synapses and pathogen invasion. Microglia in the resting state is called `Ramified', which possess long surveilling extensions with a small cell body. But, upon activation, microglia retracts the cellular extensions and transform into round migratory cells, called as `Amoeboid' state. Activated microglia undergoes actin remodeling by forming lamellipodia and filopodia, which directs the migratory axis while podosomes formed are involved in extracellular matrix degradation for invasion. Protein-aggregates in malfunctioning synapses and in CNS milieu can be detected by microglia, which results in its activation and migration. Subsequently, the phagocytosis of synapses leads to the inflammatory burst and memory loss. The extracellular nucleotides released from damaged neurons and the cytokine-chemokine gradients allow the neighboring microglia and macrophages to migrate-infiltrate at the site of neuronal-damage. The ionotropic (P2XR) and metabotropic (P2YR) purinergic receptor recognize extracellular ATP/ADP, which propagates through the intracellular calcium signaling, chemotaxis, phagocytosis and inflammation. The P2Y receptors give `find me' or `eat me' signals to microglia to either migrate or phagocytose cellular debris. Further, the actin cytoskeleton helps microglia to mediate directed chemotaxis and neuronal repair during neurodegeneration. Hence, we aim to emphasize the connection between purinergic signaling and actin-driven mechanical movements of microglia for migration and inflammation in AD. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.</p>
10aactin remodeling10aAlzheimer's disease10amicroglia10aP2Y signaling10apurinergic GPCRs10aTauopathy1 aDas, Rashmi1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/actin-mediated-microglial-chemotaxis-g-protein-coupled-purinergic-receptor-alzheimers02674nas 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-and02973nas a2200277   4500008004100000022001400041245012000055210006900175260000800244300002100252490000700273520204300280653002102323653002202344653001502366653001402381653001402395653002202409653000902431653001402440653002902454100001602483700002802499700003602527856013202563       2020                        eng d  a1759-091400aMelatonin reduces GSK3 beta-mediated tau phosphorylation, enhances Nrf2 nuclear translocation and anti-inflammation0 aMelatonin reduces GSK3 betamediated tau phosphorylation enhances  cDEC  a17590914209812040 v123 a<p>Alzheimer's disease is a neuropathological condition with abnormal accumulation of extracellular Amyloid-beta plaques and intracellular neurofibrillary tangles of Microtubule-associated protein Tau (Tau) in the brain. In pathological conditions, Tau undergoes post-translational modifications such as hyperphosphorylation by the activity of cellular kinases, which eventually leads to protein aggregation in neurons. Melatonin is a neuro-hormone that is mainly secreted from the pineal gland and functions to modulate the cellular kinases. In our study, we have checked the neuroprotective function of Melatonin by MTT and LDH assay, where Melatonin inhibited the Tau aggregates-mediated cytotoxicity and membrane leakage in Neuro2A cells. The potency of Melatonin has also been studied for the quenching of intracellular reactive oxygen species level by DCFDA assay and caspase 3 activity. Melatonin was shown to reduce the GSK3 beta mRNA and subsequent protein level as well as the phospho-Tau level (pThr181 and pThr212-pSer214) in okadaic acid-induced Neuro2A cells, as observed by western blot and immunofluorescence assay. Further, Melatonin has increased the cellular Nrf2 level and its nuclear translocation as an oxidative stress response in Tauopathy. The Melatonin was found to induce pro- and anti-inflammatory cytokines levels in N9 microglia. The mRNA level of cellular kinases such as as-GSK3 beta, MAPK were also studied by qRT-PCR assay in Tau-exposed N9 and Neuro2A cells. The immunomodulatory effect of Melatonin was evident as it induced IL-10 and TGF-beta cytokine levels and activated MAP3K level in Tau-exposed microglia and neurons, respectively. Melatonin also downregulated the mRNA level of pro-inflammatory markers, IL-1 beta and Cyclooxygenase-2 in N9 microglia. Together, these findings suggest that Melatonin remediated the cytokine profile of Tau-exposed microglia, reduced Tau hyperphosphorylation by downregulating GSK3 beta level, and alleviated oxidative stress via Nrf2 nuclear translocation.</p>
10aAlzheimer&\#821710aAnti-inflammatory10aGSK3&\#94610amelatonin10amicroglia10aneurodegeneration10aNrf210as disease10aTau hyperphosphorylation1 aDas, Rashmi1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/melatonin-reduces-gsk3-beta-mediated-tau-phosphorylation-enhances-nrf2-nuclear-translocation03043nas a2200253   4500008004100000245008900041210006900130260000900199300000700208490000700215520224100222653001002463653001502473653002402488653001402512653001402526653002202540653001802562653001402580100001602594700002802610700003602638856011502674       2020                        eng d00aPhagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia0 aPhagocytosis of fulllength Tau oligomers by Actinremodeling of a  cJAN   a100 v173 a<p>Background Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-beta plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. Methods In this study, we have prepared and stabilized hTau40(WT) oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1-sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-beta sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40(WT) oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. Results Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50 nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11(+) Iba1(high) microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. Conclusion The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.</p>
10aActin10aactivation10aAlzheimer's disease10amicroglia10amigration10aneurodegeneration10aTau Oligomers10aTauopathy1 aDas, Rashmi1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/phagocytosis-full-length-tau-oligomers-actin-remodeling-activated-microglia02423nas a2200241   4500008004100000022001400041245012900055210006900184260000800253300001200261490000700273520160700280653002101887653001901908653001501927653001401942653001401956653001401970653001801984100001602002700003602018856012702054       2021                        eng d  a1398-921900aMicroglial remodeling of actin network by Tau oligomers, via G protein-coupled purinergic receptor, P2Y12R-driven chemotaxis0 aMicroglial remodeling of actin network by Tau oligomers via G pr  cMAY  a153-1700 v223 a<p>Alzheimer's disease (AD) is associated with age-related neurodegeneration, synaptic deformation and chronic inflammation mediated by microglia and infiltrated macrophages in the brain. Tau oligomers can be released from damaged neurons via various mechanisms such as exosomes, neurotransmitter, membrane leakage etc. Microglia sense the extracellular Tau through several cell-surface receptors and mediate chemotaxis and phagocytosis. The purinergic receptor P2Y12R recently gained interest in neurodegeneration for neuro-glial communication and microglial chemotaxis towards the site of plaque deposition. To understand the effect of extracellular Tau oligomers in microglial migration, the P2Y12R-mediated actin remodeling, reorientation of tubulin network and rate of migration were studied in the presence of ATP. The extracellular Tau species directly interacted with P2Y12R and also induced this purinoceptor expression in microglia. Microglial P2Y12R colocalized with remodeled membrane-associated actin network as a component of migration in response to Tau oligomers. As an inducer of P2Y12R, ATP facilitated the localization of P2Y12R in lamellipodia and filopodia during accelerated microglial migration. The direct interaction of extracellular Tau oligomers with microglial P2Y12R would facilitate the signal transduction in both way, directional chemotaxis and receptor-mediated phagocytosis. These unprecedented findings emphasize that microglia can modulate the membrane-associated actin structure and incorporate P2Y12R to perceive the axis and rate of chemotaxis in Tauopathy.</p>
10aactin remodeling10aAlzheimer&apos10achemotaxis10amicroglia10amigration10as disease10aTau Oligomers1 aDas, Rashmi1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/microglial-remodeling-actin-network-tau-oligomers-g-protein-coupled-purinergic-receptor02456nas 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/S017193352200004802539nas 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<p>
	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.</p>
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-002637nas a2200205   4500008004100000245013100041210006900172260000800241300000700249490000700256520191300263653001402176653001402190653001402204653001302218653001802231100003602249700001602285856013002301       2023                        eng d00aMicroglia degrade Tau oligomers deposit via purinergic P2Y12-associated podosome and filopodia formation and induce chemotaxis0 aMicroglia degrade Tau oligomers deposit via purinergic P2Y12asso  cMAY  a950 v133 a<p>
	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.</p>
10aFilopodia10amicroglia10amigration10aPodosome10aTau Oligomers1 aChinnathambi, Subashchandrabose1 aDas, Rashmi  uhttps://library.ncl.res.in/content/microglia-degrade-tau-oligomers-deposit-purinergic-p2y12-associated-podosome-and-filopodia02075nas a2200229   4500008004100000022001400041245011200055210006900167260000800236300001100244490000900255520129500264653002501559653001401584653001401598653001301612653001901625100003601644700001601680700002601696856012301722       2023                        eng d  a0167-488900aTau aggregates improve the Purinergic receptor P2Y12-associated podosome rearrangements in microglial cells0 aTau aggregates improve the Purinergic receptor P2Y12associated p  cJUN  a1194770 v18703 a<p>
	Alzheimer's disease (AD) is a progressive neurodegenerative disease that is associated with protein misfolding, plaque accumulation, neuronal dysfunction, synaptic loss, and cognitive decline. The pathological cascade of AD includes the intracellular Tau hyperphosphorylation and its subsequent aggregation, extracellular Amyloid-&amp; beta; plaque formation and microglia-mediated neuroinflammation. The extracellular release of aggregated Tau is sensed by surveilling microglia through the involvement of various cell surface receptors. Among all, purinergic P2Y12R signaling is involved in microglial chemotaxis towards the damaged neurons. Microglial migration is highly linked with membrane-associated actin remodeling leading to the phagocytosis of extracellular Tau species. Here, we studied the formation of various actin structures such as podosome, lamellipodia and filopodia, in response to extracellular Tau monomers and aggregates. Microglial podosomes are colocalized with actin nucleator protein WASP, Arp2 and TKS5 adaptor protein during Tau-mediated migration. Moreover, the P2Y12 receptors were associated with F-actin-rich podosome structures, which signify the potential of Tau aggregates in microglial chemotaxis through the involvement of actin remodeling.</p>
10aAlzheimer `s disease10aFilopodia10amicroglia10aPodosome10aTau aggregates1 aChinnathambi, Subashchandrabose1 aDas, Rashmi1 aDesale, Smita, Eknath  uhttps://library.ncl.res.in/content/tau-aggregates-improve-purinergic-receptor-p2y12-associated-podosome-rearrangements