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Beta-amyloid Plaques

Alzheimer's disease is characterized by abnormal plaques and tangles in the brains of patients.
Alzheimer's disease (AD) is characterized by abnormal plaques and tangles in the brains of patients. Now, researchers at the Buck Institute for Age Research in Novato, Calif., have found that if they block specific events inside the neurons, they can prevent memory problems in mice, even when they have lots of plaques. That observation "sheds a whole new light on AD," says Dale Bredesen, who led the current study. The study was published May 2 in the Proceedings of the National Academy of Sciences. A main culprit in Alzheimer's is the beta-amyloid peptide, which forms the plaques. Beta-amyloid itself is formed when it is cleaved off a larger protein called amyloid precursor protein (APP). But other peptides are also cut from APP, including C31, which is released inside the neurons. Bredesen and colleagues reasoned that C31 might alter signaling patterns in the neurons and cause them to die. To test their model, the team engineered a change in the APP gene to block C31 release. The mutation they introduced prevents cleavage of C31 from APP in a mouse model of Alzheimer's. The team found that these mice develop large numbers of plaques but show no memory problems. Nor do the animals have synapse loss or brain atrophy as occurs in Alzheimer's. Bredesen thinks beta-amyloid starts the problem on the outside of the cell where plaques form, but that the disease process needs C31 release inside of the cell to cause destruction. The researchers already are looking for drugs that can block C31 cleavage. If they find one, they might be able to stop AD memory damage even if they cannot get rid of excess beta-amyloid.
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