Fig. 4

Propagation of Tau mediated by microglia. Tau is a microtubule-associated protein, stabilizes microtubule, and supports cargo transport. On abnormal hyperphosphorylation, Tau protein detaches from the microtubule and aggregates in the form of oligomers to further accumulate in the form of neurofibrillary tangles inside the neuron. The aggregated Tau protein, especially oligomers, has the tendency to spread within the neuron and cause template-dependent misfolding of normal Tau protein which is called seeding effect of Tau. One of the mechanisms for the spreading of Tau is exosome-mediated spreading. Exosomes are further taken up by microglia, which can either undergo degradation pathway or can be re-released in the brain environment enhancing Tau propagation. Due to the presence of aggregated Tau protein, microglia become activated and influence the inflammatory response through cytokine secretion (IL-1β, IL-6, TNF-α). The inflammatory cytokines enhance Tau pathology by reciprocating enhancement of expression of phosphorylation-dependent kinases CDK5 and GSK-3β in neuron increasing Tau hyperphosphorylation. Dietary omega-3 fatty acids repress the inflammatory response by enhancing the synthesis of lipid mediator’s resolvins and protectins by microglia. We hypothesize that the lipid mediators can resolve the inflammatory phase and hence can reduce Tau pathology by decreasing expression of Tau phosphorylating kinases