Figure 1.

Tau aggregation and spreading. (A) Tau stabilizes microtubules and contributes to the maintenance of axonal shape and neuronal morphology. In pathological conditions, tau is subjected to various posttranslational modifications (PTMs) that reduce microtubule binding and, thereby, promote the generation of insoluble tau. Soluble monomers form oligomers which aggregate to generate paired helical filaments (PHFs). These, in turn, assemble to produce neurofibrillary tangles (NFTs). (B) Possible mechanisms involved in the cell-to-cell transmission of pathological tau. Transmission may occur via direct translocation across the plasma membrane, via exosomes/synaptic vesicles, by clustering with the plasma membrane and interaction with the cell Heparan sulfate proteoglycans (HSPGs), and through cytoplasmic bridges called tunneling nanotubes. Uptake from the extracellular space can be mediated by binding and internalization with HSPGs or through endocytosis.