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2016 Grants - Grinberg
Caspases and Proteasome as Determinants of Opposite Neuronal Fate in Alzheimer’s Disease
Lea T. Grinberg, M.D., Ph.D.
University of California, San Francisco
San Francisco, California
2016 Alzheimer’s Association Research Grant (AARG)
Does an imbalance in specific nerve cell proteins lead to the formation of tau tangles in Alzheimer’s disease?
One of the hallmarks of Alzheimer’s disease is the accumulation of abnormally modified tau protein into neurofibrillary “tangles” in the brain. Tangles are thought to promote nerve cell death, but it appears that only some cells are vulnerable to damage. Recent studies have shown that proteins called caspases become activated in nerve cells during the early stages of Alzheimer’s disease. Caspases can cut tau into fragments that may promote tangle formation. However, Lea T. Grinberg, M.D., Ph.D., and colleagues found that some nerve cells do not die, even if they have high levels of activated caspases. They hypothesize that these nerve cells may be protected by complex structures called proteasomes that break down abnormal or damaged proteins.
Dr. Grinberg and colleagues have proposed a series of experiments to examine how the balance between caspases and proteasome function may determine how nerve cells respond to tau accumulation. They will determine the levels and locations of caspases, tau fragments, and proteasome-related proteins in brain tissue collected from individuals who were at various stages of Alzheimer’s disease.
To examine these processes in living cells, the research team will use a special type of cells, known as induced pluripotent stem cells (iPSCs) which can be obtained non-invasively from human adult skin or blood cells and reprogrammed into nerve cells. Using the iPSCs, the researchers can test various drugs that may target caspase or proteasome activity to prevent abnormal tau accumulation.
These studies could provide new information on how the balance of certain proteins in the brain impacts the vulnerability of nerve cells to tau-induced damage and death. Importantly this work may reveal novel targets for therapies that can prevent or slow the progression of Alzheimer’s disease.