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2017 Grants - Lee
A Novel Mechanism of Alzheimer’s Disease Signaling Pathway
Tae Ho Lee, Ph.D.
Beth Israel Deaconess Medical Center
2017 Alzheimer’s Association Research Grant (AARG)
How does the protein DAPK1 influence the production of beta-amyloid and the progression of Alzheimer’s disease?
Beta-amyloid is a protein fragment that is toxic to nerve cells and forms the main component of amyloid plaques, one of the characteristic features of Alzheimer’s disease in the brain. Beta-amyloid is produced when a larger protein, amyloid precursor protein (APP), is cut into pieces by a series of other proteins inside nerve cells.
Several lines of evidence suggest that a protein known as DAPK1 (death-associated protein kinase 1) may be involved in the processing of APP into beta-amyloid. Genetic studies show gene variants of DAPK1 are associated with late-onset Alzheimer’s. And recent studies have found that levels of DAPK1 are elevated in a high percentage of people with Alzheimer’s disease.
Tae Ho Lee, Ph.D., and colleagues have been studying how DAPK1 is involved in the Alzheimer’s disease process. In recent studies, they found evidence that DAPK1 modifies APP by attaching a chemical phosphate group (phosphorylation). Dr. Lee’s team has proposed extending their studies to determine how DAPK1 phosphorylates APP, and how that phosphorylation affects the production and accumulation of beta-amyloid. The researchers will use a strain of mice that have high levels of DAPK1 in the brain. They will measure how high DAPK1 levels affect production of beta-amyloid, the development of amyloid plaque, and learning and memory.
These studies will explore how a newly described signaling pathway in nerve cells affects the production of beta-amyloid, as well as how it affects brain function related to Alzheimer’s disease. The improved understanding of the role of DAPK1 in the disease process could help scientists identify ways to target DAPK1 with drugs to slow or halt the disease process.