Tau Master Sites: Drivers of Causative Processes in Alzheimer's Disease

Project Summary

This project aims to define the function of master sites in health and disease and test their therapeutic potential in preclinical models of Alzheimer’s disease. I aim to address following questions (1) Are master sites critical for tau hyperphosphorylation and cognitive impairment? I will ablate disease-promoting sites and study cognitive function (2) What is the physiologic role of master sites in memory? (3) Can we harness master site effects for therapeutic intervention? I will use active immunization targeting tau phosphorylation at master sites to reduce cognitive deficits. 

I have identified a unique mechanism driven by Master sites – sites on tau that predispose it to become hyperphosphorylated (a chemical change that promotes disease). I am the first to identify and investigate this concept and demonstrate how targeted inhibition of Master sites could be used to disrupt or mitigate processes underlying disease onset and/or progression. This research will have greater success in being translated into a potential therapy compared with considerable work done to date as it specifically targets the mechanism underlying tau-mediated dementia. This study will provide immediate impact by increasing knowledge on disease mechanisms and better solutions to improve or replace current therapies. This will have a significant impact on the field, thereby facilitating new collaborations that integrate the insights from this work in future studies with pharmaceutical companies to develop, research and market novel therapeutics targeting unique biomarkers. This innovative research will have great potential and global impact by providing a disease modifying treatment that would significantly benefit individuals with Alzheimer’s disease.