02138nas 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

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.

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-disease02078nas a2200229 4500008004100000022001400041245008100055210006900136260000900205300001200214490000800226520130500234653002501539653002401564653002001588653002101608653002301629100002601652700001801678700003601696856011601732 2021 eng d a0141-813000aAlpha-Linolenic acid inhibits Tau aggregation and modulates Tau conformation0 aAlphaLinolenic acid inhibits Tau aggregation and modulates Tau c cJAN  a687-6930 v1663 a

Alzheimer's disease is characterized by important patho-proteins, which being composed of Amyloid-beta, plaques and intracellular neurofibrillary tangles of Tau. Intrinsically disordered protein tau has several interacting partners, which are necessary for its normal functioning. Tau has been shown to interact with various proteins, nucleic acid, and lipids. alpha-Linolenic acid (ALA) a plant-based omega-3 fatty acid has been studied for its role as neuroprotective and beneficial fatty add in the brain. In this study, we are focusing on the ability of ALA to induce spontaneous assembly in tau protein. ALA inhibited the Tau aggregation as indicated by reduced ThS fluorescence kinetics, which indicates no aggregation of Tau. Similarly, SDS-PAGE analysis supported that ALA exposure inhibited the aggregation as no higher-order tau species were observed. Along with its ability to impede the aggregation of Tau, ALA also maintains a native random coiled structure, which was estimated by CD spectroscopy. Finally, TEM analysis showed that the formation of Tau fibrils was found to be discouraged by ALA. Hence, conclusion of the study suggested that ALA profoundly inhibited aggregation of Tau and maintained it's the random-coil structure. (C) 2020 Elsevier B.V. All rights reserved.

10aalpha-linolenic acid10aAlzheimer's disease10aFree fatty adds10aTau conformation10aTau fibrillization1 aDesale, Smita, Eknath1 aDubey, Tushar1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/alpha-linolenic-acid-inhibits-tau-aggregation-and-modulates-tau-conformation02613nas 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

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.

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-tau02570nas a2200217 4500008004100000245011000041210006900151260000800220300000700228490000700235520179900242653002102041653002402062653002402086653001702110653002202127653001902149100002602168700003602194856012202230 2021 eng d00aPhosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer's disease0 aPhosphoinositides signaling modulates microglial actin remodelin cFEB a280 v193 a

Alzheimer's disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-P contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-beta in Alzheimer's disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-beta deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.

10aactin remodeling10aAlzheimer's disease10aDietary fatty acids10aPhagocytosis10aPhosphoinositides10aPI3K signaling1 aDesale, Smita, Eknath1 aChinnathambi, Subashchandrabose uhttps://library.ncl.res.in/content/phosphoinositides-signaling-modulates-microglial-actin-remodeling-and-phagocytosis02075nas 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

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-& 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.

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