Can disease-related changes in the body’s response to stress be prevented to reduce brain levels of toxic tau protein?
Glenn Larsen, Ph.D. and Benjamin Wolozin, M.D., Ph.D.
Aquinnah Pharmaceuticals Inc
Cambridge, MA - United States
Stress granules are temporary structures that form inside cells as part of their repair response when the body undergoes injury or other types of stress. These structures interact with other molecules to prevent the overproduction of certain proteins. Once the period of stress ends, stress granules typically cease their activity. In Alzheimer’s and other brain diseases, however, persistent stress may prolong stress granules and continue to reduce protein production. Research has found that abnormally long stress granule activity can lead to the formation of abnormal proteins, including abnormal varieties of tau, that accumulate in the brain and contribute to tauopathies (tau diseases such as Alzheimer’s) and dementia.
A research team led by Drs. Glenn Larsen and Benjamin Wolozin identified a molecule that could prevent extended stress granule activity and reduce production of disease-related tau in mice. Further experiments led to the identification of two related molecules that may inhibit stress granules even more effectively and reduce the resulting tauopathy.
The investigators will now work to test the efficacy of the molecules in inhibiting stress granules and tau production. First, they will determine the optimal dose of the molecules and the most effective method of administering them in rodents. They will then assess how well the compounds reduce tau levels in genetically engineered Alzheimer’s-like mice. The researchers will also look for genetic mechanisms that may underlie the anti-tau function of their compounds. Next, they will determine whether the compounds produce any harmful side effects that may compromise their use in future human clinical trials.
The results of this project could refine our understanding of how the body’s reaction to stress may impact tau production in Alzheimer’s and other brain diseases. They may also lead to further testing of the molecules in human participants.
The Tau Pipeline Enabling Program (T-PEP) is jointly funded by the Alzheimer's Association and Rainwater Charitable Foundation.
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