Targeting the Tau-Fyn Interaction in Alzheimer’s Disease

2015  -  Birmingham, AL, USA

Grantees

Dr. Travis Rush

Organizations

University of Alabama, Birmingham

Supervising Advisor: Dr. Erik Roberson

Project summary:

As the leading cause of dementia, Alzheimer’s disease (AD) remains without cure or effective treatment. Decades of research has indicated that two proteins, amyloid-beta (Aβ) and tau, underlie the onset and progression of AD. Recent studies have linked a third protein, Fyn, to tau-dependent aspects of AD.

There is strong evidence suggesting that a direct interaction between Tau and Fyn is of specific importance in AD and a variety of evidence suggests that this interaction contributes to tau’s role in the disease. We are working to develop new therapeutics that would block this interaction. We recently completed a high-throughput screen that identified several compounds capable of blocking the Tau-Fyn interaction. The proposed research is focused on the next stage in development of Tau-Fyn interaction inhibitors, using neurons cultured from rats test the hypothesis that blocking the Tau-Fyn interaction will reduce the toxicity of amyloid-beta. If successful, our study will validate the tau-fyn interaction as important for AD progression, and contribute to the development of a novel therapeutic avenue for AD.

Final summary:

As the leading cause of dementia, Alzheimer’s disease (AD) remains without cure or effective treatment. Decades of research has indicated that two proteins, amyloid-beta (Aβ) and tau, underlie the onset and progression of AD. Recent studies have linked a third protein, fyn, to tau-dependent aspects of AD.

There is strong evidence suggesting that a direct interaction between tau and fyn is of specific importance in AD. Recently, our lab conducted a high-throughput screen to identify inhibitors of this tau-fyn interaction. This screen identified several compounds capable of blocking the tau-fyn interaction, and thereby, supported this site as a rational and valid drug target. The Weston Advisor Fellowship allowed me to begin the next phase of testing these hits. I developed several new experimental assays, using cultured neurons from rats. The use of live neurons is a more translational model of AD than the cell-free system used in the high-throughput screen, and has allowed quantification of meaningful AD-related phenotypic assays. I am using these screens to identify which of the compounds are most effective at blocking the tau-fyn interaction and protecting against Aβ-induced neuronal dysfunction/death. We are in the midst of evaluating the hits and will soon begin testing second-generation compounds that have been optimized by medicinal chemistry. Our short-term goal is to identify the most promising “probe compounds” to move forward in a mouse model of AD. With continued success, our study will validate the tau-fyn interaction as important for AD progression, and simultaneously push potential therapeutics closer to clinical trials and treating AD patients.

This project has continued through the Advisor Fellowships 2016 program | View 2016 project details