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-alzheimers03043nas 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-microglia02138nas a2200229   4500008004100000245008200041210006900123260000800192300000700200490000700207520138300214653001601597653002801613653002401641653002101665653002101686653001801707653001401725100002601739700003601765856010701801       2020                        eng d00aRole of dietary fatty acids in microglial polarization in Alzheimer's disease0 aRole of dietary fatty acids in microglial polarization in Alzhei  cMAR  a930 v173 a<p>Microglial polarization is an utmost important phenomenon in Alzheimer's disease that influences the brain environment. Polarization depends upon the types of responses that cells undergo, and it is characterized by receptors present on the cell surface and the secreted cytokines to the most. The expression of receptors on the surface is majorly influenced by internal and external factors such as dietary lipids. Types of fatty acids consumed through diet influence the brain environment and glial cell phenotype and types of receptors on microglia. Reports suggest that dietary habits influence microglial polarization and the switching of microglial phenotype is very important in neurodegenerative diseases. Omega-3 fatty acids have more influence on the brain, and they are found to regulate the inflammatory stage of microglia by fine-tuning the number of receptors expressed on microglia cells. In Alzheimer's disease, one of the pathological proteins involved is Tau protein, and microtubule-associated protein upon abnormal phosphorylation detaches from the microtubule and forms insoluble aggregates. Aggregated proteins have a tendency to propagate within the neurons and also become one of the causes of neuroinflammation. We hypothesize that tuning microglia towards anti-inflammatory phenotype would reduce the propagation of Tau in Alzheimer's disease.</p>
10aFatty acids10aMicroglial polarization10aOmega-3 fatty acids10aTau inflammation10aTau phagocytosis10aTau spreading10aTauopathy1 aDesale, Smita, Eknath1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/role-dietary-fatty-acids-microglial-polarization-alzheimers-disease02613nas a2200229   4500008004100000022001400041245010500055210006900160260000900229300001100238490000700249520182300256653002502079653002202104653001602126653002402142653001702166653001402183100002602197700003602223856012402259       2021                        eng d  a1933-691800aAlpha-Linolenic acid modulates phagocytosis and endosomal pathways of extracellular Tau in microglia0 aAlphaLinolenic acid modulates phagocytosis and endosomal pathway  cJAN   a84-1000 v153 a<p>Microglia, the resident immune cells, were found to be activated to inflammatory phenotype in Alzheimer's disease (AD). The extracellular burden of amyloid-beta plaques and Tau seed fabricate the activation of microglia. The seeding effect of extracellular Tau species is an emerging aspect to study about Tauopathies in AD. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. The excessive neuroinflammation cumulatively hampers phagocytic function of microglia reducing the clearance of extracellular protein aggregates. Omega-3 fatty acids, especially docosahexaenoic acid and eicosapentaenoic acid, are recognized to induce anti-inflammatory phenotype of microglia. In addition to increased cytokine production, omega-3 fatty acids enhance phagocytic receptors expression in microglia. In this study, we have observed the phagocytosis of extracellular Tau in the presence of alpha-linolenic acid (ALA). The increased phagocytosis of extracellular Tau monomer and aggregates have been observed upon ALA exposure to microglia cells. After internalization, the degradation status of Tau has been studied with early and late endosomal markers Rab5 and Rab7. Further, the lysosome-mediated degradation of internalized Tau was studied with LAMP-2A, a lysosome marker. The enhanced migratory ability in the presence of ALA could be beneficial for microglia to access the target and clear it. The increased migration of microglia was found to induce the microtubule-organizing center repolarization. The data indicate that the dietary fatty acids ALA could significantly enhance phagocytosis and intracellular degradation of internalized Tau. Our results suggest that microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids.</p>
10aalpha-linolenic acid10aendosomal markers10aFatty acids10aMTOC repolarization10aPhagocytosis10aTauopathy1 aDesale, Smita, Eknath1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/alpha-linolenic-acid-modulates-phagocytosis-and-endosomal-pathways-extracellular-tau