For release: Thursday, May 11, 2006
For the first time, researchers have identified a specific form of amyloid beta protein that causes memory impairment long before amyloid plaques and neurodegeneration appear in a mouse model of Alzheimer's disease (AD). The finding may lead to new ways of diagnosing and possibly even preventing the disease.
The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and reported in the March 16, 2006, issue of Nature.
Amyloid beta is the main component of amyloid plaques – abnormal clumps of protein that are found in the tissue between nerve cells in people with AD. Researchers have long suspected that amyloid plaques help to trigger the neurodegeneration and cognitive problems found in AD. Most of the known genes and other risk factors for AD increase the accumulation of amyloid beta in the brain and lead to plaque formation. However, recent studies have shown that memory problems develop long before amyloid plaques appear, and that there is no reliable correlation between the number of amyloid plaques and the amount of memory impairment in humans or mice. Other research has suggested that amyloid plaques may actually be beneficial – helping to keep toxic amyloid beta out of the way so that neurons can function. With this idea, researchers have begun to look at smaller clusters of amyloid beta peptides (protein building blocks) to see if they trigger the disease.
In the new study, Karen Hsiao Ashe, M.D., Ph.D., of the University of Minnesota, and colleagues tested mice with one of the gene defects that causes AD to see if any particular form of amyloid beta would correlate with the earliest signs of memory impairment. They found that a form of the protein called A-beta*56 (amyloid beta star 56), which is a cluster of 12 amyloid beta peptides, appeared in the brain at the same time that the mice started to show memory problems. Furthermore, the number of A-beta*56 clumps in the brain correlated with the degree of memory impairment in the mice.
The researchers then isolated A-beta*56 from the mice and injected it through tubes into the brains of healthy young rats. The rats were then tested to see how well they could remember the location of a platform in a pool of water. This is called the Morris water maze test. The researchers found that the A-beta*56 temporarily interfered with the formation of long-term memories in these rats. Before the injections, the rats could remember spatial information they'd learned. However, when the rats were given injections of A-beta*56 shortly before entering a new maze, their behavior was different. The animals initially seemed to learn with no problem, but a day later, they could not remember what they'd learned.
"A-beta*56 impaired long-term memory, but not acquisition of spatial information," says Dr. Ashe. The memory impairment was temporary and disappeared by 10 days after the injections.
The researchers found that the level of A-beta*56 in the brain was stable for many months after it first appeared, even though the transgenic mice developed more severe memory impairment as they got older. A possible explanation is that young mice can partially compensate for the toxic effects of A-beta*56 but that they lose this ability as they grow older.
While the study shows that A-beta*56 can interfere with memory, it is still not clear how it does so or whether it triggers the neurodegeneration seen later in the course of AD. The neurodegeneration may result from a different, still-unidentified problem. However, previous studies have shown that amyloid beta reduces the level of a protein called dynamin-1 that is needed for synapses to function correctly. Other research has shown that amyloid beta interferes with release of the nerve-signaling chemical called acetylcholine. Therefore A-beta*56 may prevent neurons from communicating with each other effectively. Researchers suspect that altered synaptic function could trigger neurodegeneration, although this study did not address that possibility.
The finding suggests that screening healthy people for the presence of A-beta*56 might reveal their risk of developing AD in the future and improve early diagnosis of the disease, much as cholesterol screening can reveal who is at risk of heart disease. Investigators might then be able to treat people at high risk of AD using therapies that would delay the disease or prevent it from developing. However, researchers do not yet know if A-beta*56 is present in blood or cerebrospinal fluid -- where it could be easily detected -- or if it occurs only in the brain.
The new study supports another recent finding by researchers at the University of Pennsylvania, which showed that an antibody which targets small clusters of amyloid beta can improve spatial learning and memory in a mouse model for AD. Together, the studies suggest that small clusters of amyloid beta peptides, like A-beta*56, are the cause of memory loss in the early phases of AD.
Dr. Ashe and her colleagues are now studying brains from people who died with cognitive impairment and other conditions to see if those brains contain A-beta*56, and they are looking for other proteins that may cause brain dysfunction. They also are trying to develop a blood test for A-beta*56 that could be used to screen people for risk of AD. Finally, they are looking for antibodies or drugs that might be able to block the effects of the protein or remove it from the brain. They hope to be able to conduct clinical trials of such treatments in the future.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. "A specific amyloid-beta protein assembly in the brain impairs memory." Nature, March 16, 2006, Vol. 440, pp. 352-357.
-by Natalie Frazin
Last Modified January 31, 2007