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2017 Grants - Franke
Targeting Ca2+ Dysregulation in Alzheimer's Disease
Thomas Franke, M.D., Ph.D.
New York University School of Medicine
New York, New York
2017 Alzheimer's Association Research Grant (AARG)
Does the dysregulation of calcium in the brain play a role in the development of Alzheimer's disease?
The mineral, calcium is commonly linked with bone health, but calcium (Ca2+) is in all bodily fluids and plays vital roles in the function of all cells, especially nerve and muscle cells. Because of the important role of Ca2+ in many cellular processes, the levels inside cells are tightly controlled. Ca2+ levels inside cells are important for many signaling pathways, but levels that are too low or high can cause cell death.
Beta-amyloid is a protein fragment that is toxic to nerve cells and is thought to play a crucial role in the development of Alzheimer's disease. The mechanisms by which beta-amyloid causes nerve cell damage is not completely understood. However, it is known that beta-amyloid interferes with the ability of nerve cells to control their internal Ca2+ levels and that high levels of Ca2+ activate a protein known as CaMKK2. Mounting evidence has suggested that this protein may be involved in the Ca2+-related toxicity induced by beta-amyloid.
Thomas Franke, M.D., Ph.D., and colleagues have been working with a group of collaborators to develop a drug candidate that inhibits the activity of CAMKK2. They plan to develop a series of drug candidates based on a known drug that inhibits CAMKK2, but only at very high doses. The researchers will make chemical modifications of the known drug and test each variation for its ability to inhibit CAMKK2.
Once they identify a drug that potently inhibits CAMKK2, Dr. Franke and colleagues will test how the drug affects the development of Alzheimer's changes in the brains of mice genetically altered to develop an Alzheimer's-like disease.
This research project may lead to the development of a potential drug candidate for testing its effects on the development of Alzheimer's changes in the brain. The findings will also provide new information about calcium dysregulation as one of the possible mechanisms of disease development and progression.