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2008 Grants - Wolfe
Regulation of RNA splicing in Alzheimer's and Related Dementias
Michael S. Wolfe, Ph.D.
Brigham and Women's Hospital
2008 Zenith Fellows Award
Abnormal accumulations of the protein fragment beta-amyloid and the protein tau are hallmarks of Alzheimer's disease. Beta-amyloid is clipped from its parent molecule by proteins called secretases, and it tends to form toxic clumps called plaques in Alzheimer's. Tau, a protein that normally helps maintain cell structures and transport nutrients, becomes structurally altered in Alzheimer's and tends to accumulate into neurofibrillary tangles.
Michael S. Wolfe, Ph.D., and colleagues have conducted studies that explored how beta-amyloid and abnormal tau are produced in Alzheimer's disease. They have focused on a feature called ribonucleic acid (RNA) splicing. RNA is a compound that helps produce proteins from genes. One step in this production process is the splicing, or modifying, of RNA before a gene's protein-building "instructions" can be delivered to a cell's protein-making components. Dr. Wolfe's team believes that alterations in the splicing process help produce toxic beta-amyloid and abnormal tau. Moreover, the team has found that drug-like molecules may prevent such abnormal splicing and reduce levels of the harmful proteins.
For this proposed grant, the researchers will refine these drug-like molecules and conduct more extensive experiments testing their ability to disrupt production of beta-amyloid and abnormal tau. The results of this effort could lead to novel treatments for Alzheimer's disease.