Figure 2.

Proximity‐dependent and transsynaptic mechanisms of cell‐to‐cell spread. The transmission of pathological seeds (tau: green; TARDBP‐binding protein, 43 kD (TDP‐43): red) may happen between neighboring cells within the same brain region in a proximity‐dependent pattern through active release (a) or passive leakage (c) whereas spreading between distant anatomically connected brain regions may rely on synaptic connectivity (b). The protein seeds may be released from the donor cell (gray) via exocytosis (1), packaged into vesicles such as exosomes (released from multivesicular bodies (MVBs)) (2) or dispensed by synaptic vesicles (3), with all these mechanisms having been suggested for tau and TDP‐43. Furthermore, pre‐synaptic membrane leakage because of the degeneration of neurons can lead to extracellular protein seeds (4). Once released, free protein seeds may be internalized by receptor‐mediated endocytosis (5) or heparan sulfate proteoglycan (HSPG)‐dependent macropinocytosis (6) or directly penetrate the recipient cell (blue) (7). Membrane‐coated seeds can fuse with the receiving neuronal membrane (8). Direct transfer between two cells could also happen via tunneling nanotubes (9).