Lost Memory Restored in Mice with Alzheimer's

(AD).

Investigators at Columbia University Medical Center's Taub Institute for Research on Alzheimer's Disease and the Aging Brain (New York, NY, USA) have identified an enzyme that is essential for normal cognition but that is impaired in a mouse model of AD. They found that mice regained the ability to form new memories when the enzyme's function was increased. The study was published August 25, 2006, on the website of the journal Cell.

The study suggests that enhancing the function of this enzyme, known as ubiquitin C-terminal hydrolase L1 (Uch-L1), may provide a potential strategy for treating AD and possibly reversing its effects.

In the new study, the Columbia researchers discovered that the enzyme Uch-L1 is a piece of a molecular network that controls a memory molecule called CREB, which is inhibited by amyloid beta proteins in individuals with Alzheimer's. By increasing Uch-L1 levels in mice that had AD, they were able to boost the animals' ability to create new memories.

"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 Ottavio Arancio, M.D., Ph.D., assistant professor of pathology at Columbia University Medical Center and co-principal investigator of the study with Michael Shelanski, M.D., Ph.D., chairman of the department of pathology at the Columbia University College of Physicians and Surgeons. "What makes this newly discovered enzyme exciting as a potentially effective therapy is that it restores memory without destroying amyloid beta proteins.”

The researchers assessed the memory of the mice by placing them in a cage where they were exposed to a mild stimulus when they touched the cage floor. Mice with normal memory remain still the second time they are positioned in the cage, as they recognize the place where they were first exposed to the stimulus. However, mice with Alzheimer's-like changes do not remember the place, and continue moving within the cage. When the AD mice were treated with Uch-L1, they acted like normal mice and remained still.

"While this discovery is very promising, its proven effectiveness is limited to animal models and it will take some time before it could lead to therapies in humans,” said Dr. Shelanski. "We continue to work towards that crucial goal.”



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