Understanding Tau Seeds: The Role of Protein Clumps on Membranes in Alzheimer's Disease 

This project will investigate the relationship between the shape of tau seeds and their ability to escape lysosomes and the role of membrane repair machinery in Alzheimer’s disease.

Neurodegenerative diseases like Alzheimer’s disease are caused by the buildup of clumps of proteins that spread from one part of the brain to another, causing progressive brain damage. These protein clumps can interact and disrupt the membranes responsible for containing and destroying them, causing protein clump leakage and spread. This project aims to understand the underlying cause of this membrane leakage for the development of therapies to counteract protein clump escape by promoting the repair of the membranes damaged by these protein clumps.

Lysosomal escape has been the most mechanistically intractable of the steps involved in the prion-like propagation of tau seeds. This type of problem, which is particularly recalcitrant to cellular analysis, is ideal for exploration by in vitro reconstitution with the added benefit of serving as the starting point for structural and biophysical characterization. I, and the Hurley lab, are uniquely qualified to approach this problem using in vitro reconstitution because of our expertise in membrane biophysics and structural biology, which are novel in the context of the tau propagation field.

By elucidating the mechanisms of tau seed propagation and lysosomal membrane escape, as well as identifying potential therapeutic targets, this research could pave the way for the development of novel treatments to slow or halt progression of Alzheimer’s disease and related tauopathies. Moreover, the study’s innovative approach, combining in vitro reconstitution and structural analysis techniques, promises to provide fundamental insights into tau biology, enabling the design of tailored drugs targeting specific tauopathies, thus offering more personalized and effective treatments for patients.