Microglia and exosome secretion play critical roles in the propagation of tau pathology in Alzheimer’s disease. A study published in *Nature Neuroscience* (2015) demonstrates that microglia, the primary phagocytes in the brain, facilitate the spread of tau protein through exosome secretion. The research used an adeno-associated virus (AAV) model to induce rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. Depletion of microglia significantly reduced tau propagation and excitability in the dentate gyrus, suggesting that microglia are essential for tau spread. The study also shows that microglia spread tau via exosome secretion, and inhibiting exosome synthesis reduced tau propagation in vitro and in vivo. These findings indicate that microglia and exosomes contribute to the progression of tauopathy, and that exosome secretion may be a therapeutic target. The study further reveals that microglia phagocytose and secrete tau protein in exosomes, which are then transmitted to neurons. Exosome-mediated tau transmission was confirmed in vivo, where microglia-derived exosomes efficiently transduced tau to neurons. Inhibition of exosome synthesis via pharmacological targeting of neutral sphingomyelinase-2 (nSMase2) significantly reduced tau propagation, highlighting the potential of nSMase2 as a therapeutic target. The study also shows that microglial depletion reduces the accumulation of tau in the dentate gyrus and reduces the number of activated caspase-3+ cells, indicating the pathobiological significance of tau spreading. The research highlights the role of microglia in both trans-synaptic and non-trans-synaptic pathways of tau propagation. The findings suggest that microglia are critical for the spread of tau pathology in the brain, and that exosome-mediated transmission is a key mechanism. The study provides a rapid tau propagation model that is anatomically specific and offers a valuable tool for further research into the pathogenesis of Alzheimer’s disease. The results underscore the importance of microglia and exosomes in the progression of tauopathy and suggest that targeting exosome secretion could be a promising therapeutic strategy.Microglia and exosome secretion play critical roles in the propagation of tau pathology in Alzheimer’s disease. A study published in *Nature Neuroscience* (2015) demonstrates that microglia, the primary phagocytes in the brain, facilitate the spread of tau protein through exosome secretion. The research used an adeno-associated virus (AAV) model to induce rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. Depletion of microglia significantly reduced tau propagation and excitability in the dentate gyrus, suggesting that microglia are essential for tau spread. The study also shows that microglia spread tau via exosome secretion, and inhibiting exosome synthesis reduced tau propagation in vitro and in vivo. These findings indicate that microglia and exosomes contribute to the progression of tauopathy, and that exosome secretion may be a therapeutic target. The study further reveals that microglia phagocytose and secrete tau protein in exosomes, which are then transmitted to neurons. Exosome-mediated tau transmission was confirmed in vivo, where microglia-derived exosomes efficiently transduced tau to neurons. Inhibition of exosome synthesis via pharmacological targeting of neutral sphingomyelinase-2 (nSMase2) significantly reduced tau propagation, highlighting the potential of nSMase2 as a therapeutic target. The study also shows that microglial depletion reduces the accumulation of tau in the dentate gyrus and reduces the number of activated caspase-3+ cells, indicating the pathobiological significance of tau spreading. The research highlights the role of microglia in both trans-synaptic and non-trans-synaptic pathways of tau propagation. The findings suggest that microglia are critical for the spread of tau pathology in the brain, and that exosome-mediated transmission is a key mechanism. The study provides a rapid tau propagation model that is anatomically specific and offers a valuable tool for further research into the pathogenesis of Alzheimer’s disease. The results underscore the importance of microglia and exosomes in the progression of tauopathy and suggest that targeting exosome secretion could be a promising therapeutic strategy.