Abstract
Microglia, the resident immune cells, were found to be activated to inflammatory phenotype in Alzheimer’s disease (AD). The extracellular burden of amyloid-β 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 α-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.
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Key Points
Omega-3 fatty acid elevates the resolution phase and mediates tissue repair, healing, clearing of debris and maintains homeostasis by microglia. Enhanced phagocytic nature of microglial cells due to the exposure of omega-3 fatty acids could act as a therapeutic strategy to minimize the spreading of Tau.
The extracellular Tau species after recognition by immune cells induces the immune response. Omega-3 fatty acids have the ability to effectively dampen the response given by immune cells. Dietary omega-3 fatty acids induce microglial anti-inflammatory immune response, which would enhance the clearance of extracellular pathological Tau species. In the present study, N9 microglia cells were exposed to ALA, being an omega-3 fatty acid and observed for its beneficial effects. Exposure of ALA enhanced phagocytic ability of microglia by internalizing extracellular Tau species. The effect of ALA on migration has been studied in microglia cells as they assist the phagocytosis process. The enhanced phagocytosis in the presence of ALA should also channel the internalized antigen toward lysosome-mediated degradation for the desired clearance of extracellular antigens. The degradation of internalized Tau was denoted with the endosomal markers and their colocalization with internalized Tau. The reported results suggest the beneficial effects of ALA in the brain.
The induced phagocytosis of extracellular Tau followed by its degradation via endo-lysosomal pathway shows the beneficial and neuroprotective role of ALA. This suggests the potential role of ALA to impose anti-inflammatory property of microglia in a disease condition. The phagocytosis is coupled with the degradation of internalized Tau via lysosome-mediated degradation. The phagocytosis and degradation pathway is also supplemented with enhanced migration, which extends the neuroprotective function of microglia. This indicates the potentially beneficial role of dietary supplement of ALA over Tau seeding.