Biophysically realistic network-level transport model of tau progression with exosome-mediated release and uptake processes

Abstract

The spatiotemporal progression of tau in neurodegenerative diseases like Alzheimer’s follows the brain’s structural connectome, yet a gap exists between the macroscopic spread observed over years and the protein kinetics occurring over hours. Current models fail to reconcile this disparity or incorporate the cellular mechanisms driving transmission. Here, we advance the Network Transport Model (NTM) to bridge these scales by integrating active transport along microtubules, continuous toxic tau production, and exosome-mediated release and uptake. This framework constitutes one of the most biologically detailed models of tau spread on a whole brain to date, representing a significant innovation in how multiscale proteinopathies are simulated. Simulations on the mouse connectome demonstrate that this framework replicates empirical tau propagation patterns. Our results identify trans-neuronal release and uptake rates as the primary “bottleneck” on macroscopic spread, providing a biologically grounded explanation for the disease’s slow progression. Furthermore, we find that high aggregation sequesters tau within regions, limiting global transmission, while increasing the abundance of toxic polymeric tau fibrils. Meanwhile, tau transport polarity bias (anterograde vs. retrograde) dictates spatial patterning. By linking molecular mechanics to system-wide pathology, this model provides an “in-silico” framework to evaluate how cellular-targeted interventions might alter the trajectory of tauopathic dementias.