Disease-Specific Tau Assemblies and Their Mechanisms of Cellular Propagation

Venue: Room 301, Samgatha

Disease-Specific Tau Assemblies and Their Mechanisms of Cellular Propagation

Tau protein aggregation and its spread between cells are central features of several neurodegenerative disorders, collectively known as tauopathies. Although recent structural studies have revealed that tau aggregates adopt distinct conformations in different diseases, it remains unclear whether these structural differences translate into disease-specific mechanisms of cellular interaction and propagation. In this talk, I will describe our work characterizing high-molecular-weight tau assemblies isolated from postmortem human brain tissue from Alzheimer’s disease, corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease. Using a combination of biochemical, proteomic, and cell-based approaches, we show that tau assemblies differ not only in structure, but also in isoform composition, associated protein interactomes, and functional properties relevant to cellular uptake. Notably, we find that tau assemblies derived from Alzheimer’s disease selectively engage the LRP1 receptor to promote cellular internalization, whereas assemblies from other tauopathies do not, indicating that distinct molecular pathways govern tau propagation across diseases. These findings provide mechanistic insight into how disease-specific tau assemblies interact with cells and identify the Tau-LRP1 interaction as a potential therapeutic target. I will also briefly discuss our published work showing how the molecular chaperone Hsc70 and its cochaperone CSPα maintain synaptic proteostasis by preventing aggregation of the synaptic protein SNAP‑25, providing a complementary perspective on cellular mechanisms that limit pathogenic protein assemblies.