Neuroscience
Therapeutic Neuroprotection in Alzheimer's Disease Through Controlling Toxic Astrocytes
2022 ADDF-Harrington Scholar
Non-neuronal glial cells play a vital role in the nervous system by providing physical and chemical support to neurons. In the brain, the most abundant type of glial cells, called astrocytes, have historically been viewed solely in that support role and as passive bystanders in neurodegeneration.
Recent studies, however, have identified a pathological state of toxic reactive astrocytes as a major contributor to neurodegeneration and disease progression in Alzheimer’s disease, making astrocytes an unrealized opportunity as a cellular therapeutic target.
“Astrocytes normally support healthy brain function,” Dr. Tesar said. “But we and others have now shown that in many neurodegenerative diseases astrocytes can switch into a harmful state that increases nerve cell loss and contributes to progressive neurodegeneration.”
Dr. Tesar’s lab has developed a powerful cellular platform to mimic the formation and function of toxic reactive astrocytes. He and his team have tested thousands of drugs for their ability to block the formation of toxic astrocytes, and identified a promising class of drugs that inhibit the epigenetic effector histone deacetylase 3 (HDAC3). In mouse models, inhibition of HDAC3 blocks toxic reactive astrocyte formation, favors a beneficial astrocyte phenotype, and promotes neuroprotection.
With the support of Harrington Discovery Institute, Dr. Tesar and his team are focused on optimizing and advancing new therapeutics that can inhibit HDAC3.
“We think that this project is going to allow us to identify the best-in-class molecules to move forward as therapeutics targeted at HDAC3,” Dr. Tesar said. “If successful, this could be a launching point for pushing our program forward into clinical development.”