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2017 Grants - Du
Role of N-Terminal Residues in Membrane-Mediated ABeta Assembly and Toxicity
Deguo Du, Ph.D.
Florida Atlantic University
Boca Raton, FL
2017 Alzheimer’s Association Research Grant (AARG)
How does beta-amyloid clump together and begin causing nerve cell toxicity?
Beta-amyloid (also known as ABeta) is a protein fragment at the focus of research into the causes of Alzheimer’s disease. Large numbers of beta-amyloid molecules clump together to form amyloid plaques, one of the characteristic features of Alzheimer’s in the brain. Before it forms amyloid plaque, though, beta-amyloid molecules form smaller clumps known as oligomers.
There is extensive evidence that beta-amyloid oligomers are toxic to nerve cells, and that this toxicity may play a key role in Alzheimer’s disease. Available evidence indicates that beta-amyloid interacts with the nerve cell membrane, the structure that surrounds the cells (i.e. the outer wall). This interaction is thought to promote clumping into oligomers leading to nerve cell toxicity. However, the precise mechanisms by which beta-amyloid oligomers cause nerve cell toxicity are not fully understood.
Deguo Du, Ph.D., and colleagues have proposed a series of experiments to study how beta-amyloid interacts with nerve cell membranes, and how that interaction promotes the formation of beta-amyloid oligomers. Because it is a protein fragment, beta-amyloid consists of a chain of amino acids, the chemical building blocks of proteins. Dr. Du and colleagues will explore evidence that one end of that chain (known as the N terminal) is responsible for interacting with the cell membrane.
The researchers will create altered versions of beta-amyloid with different amino acids at key locations on the N terminal. They will then study how those changes affect the ability of beta-amyloid to interact with cell membranes and then form oligomers. The researchers will also study how changes in the N-terminal amino acids affect the ability of beta-amyloid to cause nerve cell toxicity.
These studies will help scientists identify which specific regions of beta-amyloid responsible for the membrane interactions and clumping, which may then lead to toxicity. Such knowledge may help researchers develop drugs to prevent beta-amyloid toxicity in the brain.