2022 Alzheimer's Association Research Grant (AARG)
Probing the role of PTK2B-STAT3 signaling on neuronal vulnerability in AD
Can the loss of a specific protein in the brain compromise the health and activity of brain cells in Alzheimer’s?
Marcos Costa, Ph.D.
Institut Pasteur de Lille
Lille, France
Background
Glutamate is a chemical compound that helps nerve cells communicate with one another through electrical signals. According to research, nerve cells that use glutamate (known as glutamatergic neurons) may be more vulnerable to Alzheimer’s than nerve cells. Glutamatergic neurons tend to become overly active in Alzheimer’s, and this may hinder the cells’ ability to communicate, ultimately leading to memory loss and other dementia-related forms of cognitive decline.
In initial studies on brain cells grown in a laboratory dish, Dr. Marcos Costa and colleagues studied how glutamatergic neurons may become damaged in Alzheimer’s. They found that nerve cells with reduced levels of PTK2B (a gene that codes for protein tyrosine kinase 2B) showed abnormal calcium function, an indicator of cells being over active. Moreover, these abnormalities increased when the cells were exposed to beta-amyloid, a protein known to accumulate into plaques which are a hallmark brain change in Alzheimer’s. The researchers developed a three-dimensional brain-like structure (or brain organoid) that can be grown in a laboratory dish to closely resemble human brain tissue. They found that the organoid engineered to have reduced levels of PTK2B developed high levels of abnormal tau, a protein variation that contributes to tau tangles, another hallmark brain change of Alzheimer’s. They also observed that PTK2B may be activated, or “turned on”, by STAT3, a type of protein known as a transcription factor. Taken together, these findings suggest that loss of PTK2B may promote nerve cell dysfunction and cognitive decline in brain disease.
Research Plan
Dr. Costa and team will engineer glutamatergic neurons with different levels of PTK2B in (1) a laboratory dish and (2) as part of a three-dimensional brain organoid. They will study how altered PTK2B function impacts the activity and genetic make-up of the nerve cells, as well as the accumulation of abnormal tau. The researchers will also study how those changes may be linked to altered PTK2B activation by STAT3. Finally, they will engineer nerve cells with a genetic variation in PTK2B. This variation is known to increase an individual's risk of Alzheimer’s. The team will determine if these cells develop reduced PTK2B levels, as well as any changes in their activity level and the genes that are on or off.
Impact
Results from Dr. Costa’s study will help clarify how the brain cell activity, and the biological mechanism underlying this activity, promote brain changes in Alzheimer’s disease. They may also lead to novel dementia therapies that target this biology.