α- Linolenic Acid Modulates Phagocytosis of Extracellular Tau and Induces Microglial Migration

Abstract

Background The seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer’s disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory properties to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascades and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy. Methods N9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α- Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were assessed by wound-scratch assay along with Microtubule organizing center (MTOC) reorientation were studied after exposure of Tau and ALA as the property of highly migratory microglia. Results The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increased levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization and reduces the nuclear-centrosomal axis polarity and favorable anterior positioning of MTOC. Conclusions Tau seeds greatly contribute to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhances phagocytosis and intracellular degradation of internalized Tau. Enhanced migration supports the phagocytosis process. Our approach provides insights into the beneficial role of ALA as an anti-inflammatory dietary supplement to treat AD.

Interaction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation

“…These include scavenger receptors, toll-like receptors, transmembrane receptors such as integrin and Triggering receptor expressed on myeloid cells 2 reported to interact directly with amyloid-β fibrils for its activation, phagocytosis and internalization [35,65,66]. In AD, extracellular Tau species activates microglia via actin remodelling, promotes migration and phagocytosis of Tau for its clearance which could further be enhanced by other factors such as lipids and fatty acids [67][68][69]. In Tauopathy models, microglia are involved in Tau propagation, neuroinflammation and neuronal damage by the release of toxic factors and pro-inflammatory cytokines and also leads to synaptic losses [70,71].…”