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2014 Grants - Strittmatter
Signaling by ABeta Oligomer in the Post-Synaptic Density
Stephen M. Strittmatter, M.D., Ph.D.
Yale University School of Medicine
New Haven, Connecticut
2014 Zenith Fellows Award
Synapses are specialized connections between nerve cells that allow the brain to process rapid signals; they are essential for many of the brain’s unique capabilities, including learning and memory. Where a nerve cell receives a signal at a synapse, it does so at a specialized region called the post-synaptic density. Dysfunction and shrinkage of synapses, including the post-synaptic density, are some of the earliest signs of Alzheimer’s disease in the brain.
When a post-synaptic density receives a signal, it can generate several signals of its own, including rapid electrical signals and slower biochemical signals inside the receiving nerve cells. Impairments in both types of signals have been implicated in Alzheimer’s disease.
Stephen Strittmatter, M.D., Ph.D., and colleagues have been studying how biochemical signals at the post-synaptic density may be altered in Alzheimer’s disease. They have shown that a protein on the outer surface of the post-synaptic density, known as mGluR5 (the metabotropic glutamate receptor 5), may be involved in the impairment of synapses during the disease process. The mGluR5 receives signals from other nerve cells and begins the process of biochemical signaling in the receiving nerve cell. It may also mediate the damaging effects of beta-amyloid, a protein fragment implicated in detrimental brain changes in Alzheimer’s disease.
Dr. Strittmatter and colleagues have proposed to study how mGluR5 connects to another protein known as Fyn, which relays the damaging effects of beta-amyloid to other components of the cell’s machinery. Dr. Strittmatter’s team will investigate whether drugs that block mGluR5 can alleviate the loss of synapses in mice genetically altered to have an Alzheimer’s-like condition. They will also study the mGluR5 biochemical pathway in brain tissue from people who had Alzheimer’s disease. These studies may help to identify new targets for drugs to slow or halt the progression of synapse loss in Alzheimer’s disease.