Fig. 6.

Scheme of the potential mechanisms underlying the reduction of tau pathology via targeting microglial P2RX7 in tau transgenic mouse model. a. Tau aggregates may spread trans-synaptically if the synapses are intact. However, in case of tau accumulation, synapses are inactivated and subjected to microglial sensing and pruning in disease conditions. Phagocytosed synapses contain tau aggregates, which will be transported through endosomal pathways, and many of them will be digested through the endolysosomal pathway. In parallel, tau aggregates in the late endosome will be incorporated into the ILVs of MVBs, which will be secreted as exosomes and propagated into nearby neurons. P2RX7 mediates secretion of both exosomes and microvesicles. b. Inhibition of P2RX7, mainly expressed in microglia, reduces secretion of EVs and potentially enhances intracellular clearance of tau through endolysosomal degradation, suppressing the microglia-mediated tau propagation in P301S mice