Enzyme helps cancel effects of Alzheimer's

Friday, August 25, 2006 Tests were conducted with mice and with brain slices. SCRIPPS HOWARD Increasing levels of a key housekeeping enzyme in the brains of mice with a rodent form of Alzheimer's disease successfully restored memory and nerve cell function, according to a new study. Although only demonstrated in an animal model, the work could point to a promising strategy for battling the debilitating disease and perhaps even reversing its effects in humans. The research was published online Thursday by the journal Cell. All currently available therapies against Alzheimer's have targeted amyloid beta, the protein responsible for the amyloid plaques that tangle neurons in the brains of patients with the disease. Columbia University researchers focused on newly discovered aspects of an enzyme called ubiquitin C-terminal hydrolase (Uch-L1). It is part of a network that controls a memory molecule that is inhibited by amyloid proteins. Ubiquitin is a "tag" that marks proteins for destruction by the cellular "garbage disposal" system known as the proteasome. Uch-L1 serves as a gatekeeper to this system by removing the tag to allow the breakdown of protein to start. What happened "By injecting what is essentially a Uch-L1 drug to raise its levels in the brain, we were able to restore a great deal of brain activity in a transgenic mouse model of Alzheimer's," said Dr. Michael Shelanski, co-author of the study and chairman of the pathology department at Columbia's College of Physicians and Surgeons. "While amyloid beta is certainly a key player in Alzheimer's disease, and efforts to reduce it remain a worthy goal, our results show that even in the presence of the plaque, damage to memory can be reversed." The researchers tested the mice's memory by putting them in a cage where they got a mild shock when they touched part of the floor. Mice with normal memories remained still the second time they were placed in the cage, because they recognized the spot and remembered what happened before. Mice with brain changes similar to Alzheimer's effects didn't remember and continued to move around. But after those animals were treated with the enzyme, they acted like normal mice again. In another test, the scientists treated brain slices with a chemical that blocked the enzyme's function. That brain tissue proved less likely to form and strengthen nerve connections that are the basis of learning and memory. But when the tissue was treated to restore Uch-L1 levels, the deficits in nerve transmission were corrected. "Because the amyloid beta proteins that cause Alzheimer's may play a normal, important physiological role in the body, we can't destroy them as a therapy," explained Dr. Ottavio Arancio, an assistant professor of pathology at Columbia and co-author of the report. "What makes this newly discovered enzyme exciting as a potentially effective therapy is that it restores memory without destroying amyloid beta proteins."