To view an abstract, select an author from the vertical list on the left.
2015 Grants - Mobley
Enhanced APP Processing to Prevent Alzheimer Pathogenesis in Down Syndrome
William C. Mobley, M.D., Ph.D.
University of California, San Diego
La Jolla, California
2015 Understanding the Development and Devising Treatments for Alzheimer’s Disease in Individuals with Down Syndrome Grant
Can a novel drug candidate that decreases toxic amyloid precursor protein fragments help prevent or reduce Alzheimer’s-like brain changes?
Down syndrome is a condition in which people are born with an extra copy of chromosome 21. Chromosomes contain all of our genes, and scientists believe that the extra copies of genes on chromosome 21 lead to health issues associated with Down syndrome. People with Down syndrome have a high risk of developing Alzheimer’s disease, and the disease often begins to develop when the individuals are in their 30s and 40s.
One of the chromosome 21 genes that may link Down syndrome and Alzheimer’s is the gene that codes for amyloid precursor protein (APP). APP is the parent protein of beta-amyloid, a protein fragment that accumulates into amyloid plaques, one of the key features of Alzheimer’s disease. Recent studies have shown that APP and the protein fragments it creates, including beta-amyloid, may block neurotropic factors in nerve cells. Neurotropic factors are molecules that promote the health and survival of nerve cells. In people with Down syndrome, high levels of APP in the brain may contribute to the development of Alzheimer’s disease by both increasing the build-up of beta-amyloid and by hindering neurotropic factors needed for normal nerve cell function.
William C. Mobley, M.D., Ph.D., and colleagues have proposed a series of studies to explore the effects of a novel drug candidate that modulates the activity of a protein complex known as gamma-secretase, which is one of many molecular “scissors” responsible for processing APP. Initial studies using cells grown in laboratory dishes found that this compound can decrease the levels beta-amyloid and other APP-generated protein fragments. The researchers plan to study how this compound affects the levels of APP fragments in the brains of mice that have been genetically engineered to develop a condition similar to Down syndrome. Once they determine the optimal dose of the compound to use, they will test how it affects memory function and the survival of nerve cells in these mice.
These studies represent a first step in the development of a drug candidate that targets some of the fundamental brain changes associated with Alzheimer’s disease. The results of this work will help provide the data needed to move this potential treatment closer to human clinical trials. If successful, this drug could be used in the prevention or treatment of Alzheimer’s disease in people with and without Down syndrome.
Co-funded by the Alzheimer’s Association, Global Down Syndrome Foundation and Linda Crnic Institute for Down Syndrome