Two plausible transmission mechanisms of misfolded tau across synapses. Having hyperphosphorylated tau (blue dots) and misfolded tau (red dots) at opposing sides of the synapse may create an opportunity for spreading tauopathy. The infectious species, likely to be oligomers (red irregular shapes), may either transmit by (A) vesicular trafficking, or (B) debris uptake. In (B), as tauopathy damages a neuron to inflict neurite degeneration, tau oligomers may be incompletely degraded and remain as debris in the extracellular space. The neighboring synaptic terminal may accidentally endocytose the debris containing tau oligomers, seeding further tau misfolding.