Fig. 2

Transcellular transfer of tau: potential mechanisms underpinning this process. Tau proteins can be transferred from donor cells (green) to recipient cells (orange) using different routes. This figure highlights different pathways reported (blue or violet arrows) or hypothesized (red arrows) in the literature. Whether these pathways are used for physiological transfer of tau proteins to subserve as yet unknown functions of normal tau, or are pathological routes for transfer of tau seeds that can propagate transcellular transfer of tau aggregation, remains to be resolved. Pathway indicated by blue arrows - tau proteins are released in the medium by extracellular vesicles like exosomes and ectosomes. It is unclear how tau proteins carried inside vesicles reach the cytoplasm of recipient cells (Q1). Violet pathway- Around 90% of tau in the extracellular space is found as free protein. The mechanism(s) by which tau reaches the extracellular space in free form is unknown. Passive diffusion facilitated by a membraneous transporter/receptor (Q2) or active exocytosis (Q3) might contribute to this process. Uptake of free tau species by recipient cells, including HSPG or APP-mediated endocytosis/ macropinocytosis of tau accumulates have been reported. Whether free or aggregated tau is taken up by other mechanisms such as diffusion (Q4) or non-receptor mediated endocytosis/macropinocytosis (Q5) has not been resolved. Nor is it known how membrane-bound tau can escape from vesicles and enter the cytoplasm of recipient cells (Q6). Orange pathway- Tau was shown to be present inside nanotubes connecting cells in vitro and to allow its interneuronal transfer. This mechanism could potentially participate in prion-like propagation of tau pathology but whether it is a mode of transcellular transfer of seeding-competent tau species in vivo needs to be investigated