Prion Drugs for Alzheimer’s Disease Therapy
Stephen Strittmatter, MD, PhD
Yale University School of Medicine (New Haven, CT)
July 1, 2013 to June 30, 2016
Grant Reference ID:
Prion Protein Antagonists for Alzheimer’s Therapy
In Alzheimer's disease (AD), chemical connections (synapses) between neurons are damaged and cognition is impaired. Dr. Strittmatter’s team has found that beta-amyloid (Abeta) binds to prion protein at synapses to trigger this process. Here, the team seeks to discover and validate drugs that protect prion protein from Abeta and thereby prevent the initiation of AD malfunction.
When this study is complete, Dr. Strittmatter’s team will have determined whether drugs blocking prion protein have potential use as a therapy for Alzheimer’s disease (AD). In AD, the beta-amyloid (Abeta) protein builds up. Specific collections of Abeta, termed oligomers, damage neurons and cause memory loss. To attack nerve cells, Abeta first binds to prion protein on the cell surface. The team seeks to identify and optimize drug-like compounds that prevent Abeta from binding to prion protein. Then, they will test if these compounds can reverse memory loss in mouse models of AD. If so, these compounds will be starting points for testing in the clinic to preserve memory function in AD.
Many drug trials have tried to alter the level of Abeta, but Dr. Strittmatter’s team’s approach is unique in that they seek to prevent the toxic effect of Abeta to nerve cells. The team believes that this distinction provides the opportunity for greater effects than the approaches now being tested in the clinic that focus on the amount of Abeta.
At the end of the proposed work, Dr. Strittmatter will have determined whether drug-like compounds can target the Abeta interaction with prion protein and whether this reverses memory loss in animal models of Alzheimer’s disease. Positive results in these experiments will set the stage for a full clinical drug development effort targeting prion protein for AD therapy.
About the Researcher
Stephen M. Strittmatter, M.D., Ph.D., was born in St. Louis, MO and earned his undergraduate degree from Harvard College, summa cum laude. He completed M.D. and Ph.D. training at Johns Hopkins in 1986 with mentorship from Solomon H. Snyder, M.D. He then moved to Massachusetts General Hospital for a medical internship and an Adult Neurology residency. While at MGH, he worked as a Research Fellow with Mark Fishman, M.D. exploring the molecular basis of axonal guidance. He joined the faculty of Yale University in 1993. He currently holds the Vincent Coates Professorship of Neurology at Yale and is a Founding Director of the Yale Cellular Neuroscience, Neurodegeneration and Repair Interdepartmental Program.
Over 20 years, his work has contributed to defining a molecular basis for axonal guidance during development and neural repair after adult injury. Dr. Strittmatter identified the axon growth inhibitor, Nogo, as well as an axonal receptor for Nogo and MAG. He has demonstrated the role of this pathway in limiting recovery from spinal cord injury and stroke, with therapeutic implications. His laboratory is particularly interested in the interplay between endogenous plasticity and recovery from injury.
During the last 4 years, his laboratory has also explored ligand-receptor interactions in degenerative dementias. He has focused on the pathophysiological action of Amyloid-beta (Aβ) peptide oligomers in Alzheimer's disease, and on the role of secreted Progranulin in Fronto-Temporal Lobar Degeneration. Dr. Strittmatter has indentified PrPC and Sortilin as sites for Aß and Progranulin, respectively. He utilizes receptor ligand binding assays, expression cloning, electrophysiology, genetics and mouse behavior to study these pathways.
Dr. Strittmatter’s research has been recognized by the Ameritec Award, John Merck Scholar Award, Donaghue Investigator Award, McKnight Foundation Brain and Memory Disorders Award and Senator Jacob Javits Award in the Neurosciences.
Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, Robinson SA,
Gunther EC, van Dyck CH, Nygaard HB, Strittmatter SM. Fyn inhibition rescues
established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015 Feb 23.
doi: 10.1002/ana.24394. [Epub ahead of print]
First published on: Monday, July 1, 2013
Last modified on: Friday, July 1, 2016