Fig. 8

Summary of nSMase2’s role in EV-mediated tau propagation. Under normal MVB conditions, nSMase2 is active at basal levels with moderate ceramide levels. With tau expression, nSMase2 activity is increased and ceramide levels rise, leading to the invagination of the MVB membrane, forming more ILVs and trapping tau within, which are then released to the extracellular space as EVs carrying tau (black, upper pathway). These EVs can then pass on tau to naïve, healthy neurons, thus propagating the disease. With PDDC (blue, lower pathway), nSMase2 is inhibited and the amount of ceramides is reduced, forming fewer ILVs and trapping less tau which causes fewer naïve, healthy neurons to become seeded