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2020 Tau Pipeline Enabling Program (T-PEP)

Bifunctional tau degraders as a novel therapeutic strategy for tauopathy

Could a new chemical compound help destroy modified tau and protect nerve cells from damage?

Stephen Haggarty, Ph.D.
Massachusetts General Hospital
Boston, MA - United States


The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer’s, frontotemporal dementia and over 20 other brain diseases the shape of tau protein becomes modified or “misfolded” and this could contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. 

Dr. Stephen Haggarty and colleagues are developing small “bifunctional” chemical compounds to degrade, or destroy modified tau inside nerve cells. The compounds have two functions: one end attaches to modified tau, while the other attaches to a protein that acts as a “signal” to nerve cells that the modified tau should be destroyed. The researchers have administered these compounds to cells from people who had tau-related brain diseases. Preliminary results show that the compounds successfully prevented modified tau from damaging the nerve cells inside laboratory dishes, while still allowing healthy tau to perform its important functions.

Research Plan

Dr. Haggarty’s team will continue to refine their chemical compounds to make them more potent, stable, and promising for therapeutic use. The researchers will test the compounds’ ability to destroy different types of modified tau, using nerve cells growing inside laboratory dishes, and three-dimensional brain-like structures grown from the cells of individuals with  genetic variations that may increase the risk of tauopathies like Alzheimer’s. They will also administer molecules to animal models to determine safe, effective doses for future studies and determine their ability to enter the blood brain barrier (a highly selective barrier that filters large particles from the blood and does not allow them to enter the brain). These are key steps to moving these compounds forward as possible therapies.


This study may refine previously developed chemical compounds and potentially identify new compounds to reduce modified tau levels in the brain during Alzheimer’s and other tau-related brain diseases. If successful, results from this work could serve as a foundation for future clinical trials to test whether these compounds may be effective in humans.

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