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Brain receptor key to curing Alzheimer's.

A tiny piece of a crucial receptor-NMDA (N-methyl-D-aspartate)--that fuels the brain and without which sentient beings cannot live has been discovered by University at Buffalo (N.Y.) scientists as a promising new drug target for Alzheimer's and other neurodegenerative diseases.

"This is the first time that this site has been shown to be useful as a drug target," declares Gabriela K. Popescu, associate professor of biochemistry and senior author on the study. "If we could find a drug that attaches itself to this site and then locks together NMDA receptor subunits, that would be huge for fighting disability from stroke and Alzheimer's and other neurodegenerative diseases."

The research focuses on the brain's receptors for the neurotransmitter, glutamate, which is implicated in these diseases as well as in other conditions, such as glaucoma.

The two main glutamate receptors in the brain are NMDA and AMPA receptors, which play critical roles in human learning and memory Both types are made of four subunits and, within each receptor, these subunits are organized in pairs called dimers.

"Because these receptors are so similar in structure, it was assumed that they function in much the same way, but when we altered the dimer interface, the site where two subunits come together within each pair, we found that the NMDA receptor works just the opposite of the way that the AMPA receptor works," points out Popescu. "Cementing this interface in AMPA receptors leads to more activity, whereas we found just the opposite to be true in NMDA receptors."

By locking the subunits together, the researchers were able to achieve a marked reduction in NMDA activity and, subsequently, in the amount of calcium that enters neurons in response to the neurotransmitter glutamate. Calcium overload due to overactive NMDA receptors is what eventually kills off neurons, leading to the symptoms that occur after a stroke and in Alzheimer's and other neurodegenerative diseases.

"The fact that by cross-linking the subunits we could so dramatically reduce NMDA receptor activation demonstrates, for the first time, the tantalizing possibility that we may be able to develop new therapies that can much more effectively treat, or even one day prevent, some of these devastating diseases, like Alzheimer's and stroke," concludes Popescu.

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Title Annotation:Neurology; N-methyl-D-aspartate
Publication:USA Today (Magazine)
Geographic Code:1USA
Date:Feb 1, 2012
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