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2011 Grants - Wang
Nicotinic Alpha7-NMDA Receptor Interactions in the Aged Nonhuman Primate
Min Wang, Ph.D.
New Haven, Connecticut
2011 New Investigator Research Grant
The protein fragment beta-amyloid tends to accumulate in the brains of people with Alzheimer's disease. Early accumulations of beta-amyloid called oligomers may be the most toxic amyloid forms in dementia. A recent study with mice found that oligomers exerted their toxicity through two kinds of receptors, or cellular docking sites. One of these receptors is called the alpha-7 nicotinic acetylcholine receptor (a7nAchR). It is a docking site for cholinergic neurons, which participate in many learning and memory functions. The other receptor type, called the N-methyl-D-aspartate (NMDA) NR2B receptor, is a docking site for glutamate, a chemical messenger in the brain. Study researchers found that stimulation of the nicotinic receptor was associated with oligomer-induced damage to NMDA receptor function. This loss of function, in turn, hindered the ability of neurons to communicate with one another and caused memory problems in the mice.
Min Wang, Ph.D., and colleagues have obtained similar findings from a study with aging monkeys. They showed that toxic interactions between beta-amyloid and the two receptors occurred in their animals' prefrontal cortex, an area of the brain thought to support working memory. This form of memory involves the temporary storage of information for cognitive tasks.
For this study, Dr. Wang and colleagues will try to confirm and extend their earlier results. Using elderly monkeys with high brain levels of beta-amyloid, the researchers will examine whether stimulation of nicotinic receptors may lead to amyloid-induced losses of NMDA NR2B activity. The team will also examine whether NMDA functioning can be restored in these monkeys by administering a drug that deactivates a7nAchR. The results of this effort could confirm a novel mechanism by which beta-amyloid causes cognitive decline in Alzheimer's disease. They could also lead to new treatment strategies for people with Alzheimer's, many of whom are taking cholinergic drugs that increase a7nAchR stimulation which may inadvertently hasten disease progression rather than slow it.