The Journal of Neuroscience, 2001, 21:RC120:1-5
RAPID COMMUNICATION
-Amyloid1-42 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 (A1-42). 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 A1-42 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 A1-42 inhibition is dependent on the nAChR channel
subtype expressed. Thus, chronic inhibition of cholinergic signaling by A1-42 could contribute to the cognitive deficits
associated with AD.
Key words:
postsynaptic; photolysis; caged-carbachol; stratum
radiatum; interneurons; acetylcholine
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