OHSU study aims to halt Alzheimer’s by blocking enzyme

Inhibiting gamma secretase may prevent amyloid plaque build-up thought to trigger disease, but trials continue Oregon Health & Science University is participating in a national study of a drug that may prevent Alzheimer’s disease by blocking an enzyme that produces plaques believed to trigger the disorder. OHSU is one of six sites around the country taking part in a double-blind, placebo-controlled study of the agent known as LY450139, a gamma secretase inhibitor manufactured by Indianapolis-based Eli Lilly and Co. Other study sites are in Indianapolis, St. Louis, Philadelphia, Seattle, and La Jolla, Calif. Lilly is funding the study. Gamma secretase is an enzyme that produces beta-amyloid by snipping a fragment of the protein from a larger protein that extends across the plasma membrane of the cell. The beta-amyloid fragments clump together to form dense, insoluble plaques inside the hippocampus, a curved, elongated ridge deep in the brain that controls learning and memory, and the cerebral cortex, the surface layer of gray matter of the cerebrum where sensory and motor information is coordinated. The gamma secretase enzyme is made up of a complex of four proteins, and LY450139 is thought to de-activate it by binding within the complex, although the exact location is still being studied. "There is a theory that beta-amyloid produces Alzheimer’s disease, so if you stop the amyloid, you stop the disease," said Joseph Quinn, M.D., associate professor of neurology, and cell and developmental biology, OHSU School of Medicine and the Portland Veterans Affairs Medical Center. He also is an investigator at OHSU’s Layton Aging & Alzheimer’s Disease Center.