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2012 Grants - Diwan
Enhancing Lysosome Biogenesis to Prevent Amyloid Plaque Pathogenesis
Abhinav Diwan, M.D.
St. Louis, Missouri
2012 New Investigator Research Grant
Lysosomes are small structures inside cells that specialize in breaking down unwanted proteins and other cellular components. These "waste" components could potentially damage or kill the cell. One biochemical process that lysosomes use to accomplish their task is called the autophagic-lysosomal pathway. Malfunction of lysosomes in general, and the autophagic-lysosomal pathway in particular, have been implicated in several neurodegenerative disorders, including Alzheimer's disease. Impaired lysosomal function can lead to the overproduction of beta-amyloid from its parent molecule, amyloid precursor protein (APP). Beta-amyloid is a protein fragment closely linked to Alzheimer's pathology.
Recent studies have found that the production and activities of lysosomes are partly regulated by a transcription factor called TFEB. Transcription factors affect cellular activity by influencing how genes are expressed in the cells. In preliminary experiments, Abhinav Diwan, M.D., and colleagues have observed that when cancer cells expressing APP are engineered to express TFEB as well, these cells produce lower levels of beta-amyloid in culture. The researchers hypothesize that TFEB stimulates the autophagic-lysosomal pathway, which in turn prevents APP from generating beta-amyloid fragments.
For this study, Dr. Diwan and colleagues will conduct more extensive tests to assess TFEB's role in moderating beta-amyloid production. First, they will attempt to confirm their earlier results in the laboratory. Then the team will inject TFEB into the brains of mice genetically engineered to express Alzheimer's-like symptoms. These mice will be analyzed to determine whether TFEB treatment prevented the growth of beta-amyloid plaques (or clumps) in their brains. The results of this work could lead to targeted, lysosome-based therapies for Alzheimer's disease in people.