Fig. 3

Phenotypic response of microglia on dietary fatty acid exposure. Spreading of Tau between the neurons in tauopathies is a major concern to address that increases the disease progression. The aggregated species of Tau, prudentially oligomer species of misfolded aggregated Tau, show more propagation in the brain environment and found to be more toxic. The phenotype of microglia driven by omega-3 fatty acids could be used as a therapeutic strategy to prevent the propagation of extracellular Tau in tauopathies. Microglia has ramified morphology in surveillant mode, and they significantly express Fc receptors, P2Y6R, β-2 integrins, and PRRs including RAGE and TLRs. Ramified state is maintained through inhibitory signal through interaction of CD200-CD200R, CD22-CD45, and CX3CL1-CX3CR1. Saturated fatty acid (palmitic acid, stearic acid) triggers TLR-4 signaling leading to increase in pro-inflammatory cytokine production (TNF-α); omega-6 fatty acid (arachidonic acid) activating the pathway of PKCδ causes phosphorylation of Tau increasing the aggregation of protein in cells. Thus, it favors inflammatory phenotype and also enhances aggregation of Tau in AD, whereas unsaturated omega-3 fatty acids trigger phagocytic response through TREM2 that recognizes apoptotic bodies and further activates ERK pathway to increase the clearance of apoptotic bodies. P2Y6R receptors interact with UDP released from dead neuron (act as an eat-me signal), which increases phagocytosis of debris, accumulated proteins, and pathogens. This is also indicated by increase in expression of Arginase-1 (Arg-1) and chitinase-like-3 (Ym1) and increases anti-inflammatory cytokine production (TGF-β, IL-4). Along with their anti-inflammatory properties, they also regulate wound healing through Arg-1 and Ym1. Therefore, omega-3 unsaturated fatty acids favor anti-inflammatory phenotype that can mediate clearance of extracellular Tau in tauopathies