Basic Science and Pathogenesis.

Background: Tauopathies are a class of neurodegenerative diseases marked by tau protein spread and aggregation. Recently, our group described the cellular receptor Low-density lipoprotein Receptor-related Protein 1 (LRP1) as a regulator of tau spread. Knockdown of LRP1 halts tau spread in human induced pluripotent stem cell-derived neurons and the mouse brain, indicating potential therapeutic implications. However, a comprehensive understanding of the tau-LRP1 molecular complex remains elusive.

Method: Our research focuses on elucidating the tau-LRP1 structural interface and investigating how tau aggregate structure influences LRP1 processing. We are using covalent-labeling mass spectrometry to map the tau-LRP1 interface in vitro and in cells. We are isolating brain-derived tau oligomers from various tauopathies and measuring their dependence on LRP1 using cell culture models of tau propagation.

Result: Our results have identified residues critical for the interaction between tau and LRP1. Further, we have determined that brain-derived tau oligomers utilize LRP1 for their endocytosis and that this is potentially dependent on structural elements of tau oligomers.

Conclusion: Our work provides insights into the structural aspects underlying tau-LRP1 interactions and lays the groundwork for the design of potential disease therapeutics.