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The Journal of Neuroscience, 2001, 21:RC120:1-5

RAPID COMMUNICATION
-Amyloid_1-42 Peptide Directly Modulates Nicotinic Receptors in the Rat Hippocampal Slice

D. L. Pettit, Z. Shao, and J. L. Yakel

National Institute Of Environmental Health Sciences, National Institutes of Health, Laboratory of Signal Transduction, Research Triangle Park, North Carolina 27709

Alzheimer's disease (AD) is a human neurological disorder characterized by an increasing loss of cognitive function and the presence of extracellular neuritic plaques composed of the -amyloid peptide (A_1-42). However, the link between these molecular correlates of AD and the loss of cognitive function has not been established. The pathology associated with AD includes the loss of basal forebrain cholinergic neurons, presynaptic terminals in the neocortex and hippocampus, and a decrease in the total amount of neuronal nicotinic acetylcholine receptors (nAChRs). This leads to the hypothesis that failure in the cholinergic system underlies the dementia seen in AD. Cognitive performance has been linked to nAChR function in the hippocampus, and the interneurons expressing nAChRs coordinate the activity of large numbers of principal cells and therefore have a powerful role in the regulation of hippocampal activity. We have found that A_1-42 inhibits whole-cell and single-channel nicotinic currents from rat hippocampal interneurons by directly blocking the postsynaptic nAChR channels at concentrations as low as 100 nM. This inhibition appears specific for peptide sequence and neuronal nAChRs, and the magnitude of A_1-42 inhibition is dependent on the nAChR channel subtype expressed. Thus, chronic inhibition of cholinergic signaling by A_1-42 could contribute to the cognitive deficits associated with AD.

Key words: postsynaptic; photolysis; caged-carbachol; stratum radiatum; interneurons; acetylcholine

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Copyright © 0000 Society for Neuroscience  0270-6474/00/$05.00/0

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