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
The establishment of Tau as a factor of neurotoxicity and neuroinflammation is still a matter of debate, but recently accepted concept of Tau as a prion-like protein supports this hypothesis. The spreading of Tau and its ability to cause template-dependent deformation in the healthy neuron can be targeted. Omega-3 fatty acids are found to implement the suppression of neuroinflammation and trigger polarization of microglia. 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.
Microglia activation leads to polarization and migrates in a particular direction, depending upon the directional clues. Cytokines and chemokines response to play an important role in migration and polarization of microglia through CX3CL1-CX3CR1, IL-4, CCR5, CCR3, and CCR1-mediated signaling. The polarized state of microglia is maintained by the cytoskeletal network wherein actin provides directional sensing and microtubule dynamics for the mechanical strength to move cell forward. In this study, the enhanced phagocytosis in the presence of ALA and subsequent degradation of internalized Tau, which was confirmed by Rab5, Rab7, and LAMP2A was shown. On the other hand, ALA can improve migration profile of microglia that might help the phagocytosis process.
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.