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2010 Grants - Fondell
T3-Dependent Silencing of Beta-Amyloid Precursor Protein Gene Expression
Joseph D. Fondell, Ph.D.
University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School
Piscataway, New Jersey
2010 Investigator-Initiated Research Grant
An important focus of research into the causes of Alzheimer's disease is the protein fragment beta-amyloid, which is known to be toxic to nerve cells and to aggregate into amyloid plaques. Beta-amyloid is produced when amyloid precursor protein (APP) is cut into pieces. Recent research has found evidence that expression of APP is inhibited by thyroid hormone (T3). Because T3 levels decline during aging, these recent results suggest that declining levels of T3 may lead to increased expression of APP, and subsequent increases in levels of beta-amyloid in the brain.
Joseph D. Fondell, Ph.D., and colleagues are studying the molecular mechanisms by which T3 regulates expression of APP. Their preliminary studies suggest that T3 binds to receptors inside of nerve cells, and that these receptors then bind to specific segments of DNA, thereby controlling expression of the APP gene. The researchers plan to confirm and extend these results to identify and characterize other proteins that assist in this process. They will also identify other factors and biochemical pathways that regulate the expression of the APP gene and that influence the effect of T3. These studies will be performed using rat brain cells growing in culture. Dr. Fondell's research could lead to the development of drugs that inhibit the expression of APP in older individuals in much the same way as T3 does in younger persons. They may also help scientists identify biochemical changes that can be used to diagnose and monitor Alzheimer's disease.