The puzzling behavior of a key enzyme has been explained and this may pave the way toward a possible treatment for a rapidly progressing form of Alzheimer’s disease (AD). Butyrylcholinesterase (BChE) breaks down the neurotransmitter acetylcholine and is associated with the neurofibrillary tangles and amyloid plaques that characterize AD. People with a particular mutation of the BChE gene, called the BChE-K mutation, are prone to more rapid development of AD than are those with the normal gene. This has been a puzzle because, in theory, the carriers of the mutated gene should be more protected from the devastating effects of the disease, because the mutated BChE breaks down acetylcholine at a slower rate than does the normal BChE. The result is that the mutation carriers maintain higher levels of this neurotransmitter, so they should, in principle, be protected from AD, in which acetylcholine levels decrease. In the current work, researchers at the Hebrew University of Jerusalem, and collaborating institutions, found that the mutation in the BChE-K gene damages the very end, or tail, of the resultant mutant protein. This tail is the part of BChE which is important for protection from the AD plaques. The tail does this by interacting with the AD beta-amyloid protein and preventing it from precipitating and forming the AD plaques. Thus, it seems that the K mutation can be both neuroprotective by sustaining acetylcholine levels and neurodegenerative by inefficiently interfering with the formation of AD plaques. To compare the normal protein to the K mutant, the researchers used synthetic tails of the normal and the K proteins, as well as engineered human BChE produced in the milk of transgenic goats. The goat-produced protein is prepared for the U.S. military as protection from nerve gas poisoning.
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