beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice

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 beta -amyloid peptide (A beta (1-42)). How ever, the link between these molecular correlates of AD and the loss of cog nitive function has not been established. The pathology associated with AD includes the loss of basal forebrain cholinergic neurons, presynaptic termi nals in the neocortex and hippocampus, and a decrease in the total amount o f neuronal nicotinic acetylcholine receptors (nAChRs). This leads to the hy pothesis that failure in the cholinergic system underlies the dementia seen in AD. Cognitive performance has been linked to nAChR function in the hipp ocampus, 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 beta (1-42) inhibi ts whole-cell and single-channel nicotinic currents from rat hippocampal in terneurons by directly blocking the postsynaptic nAChR channels at concentr ations as low as 100 nM. This inhibition appears specific for peptide seque nce and neuronal nAChRs, and the magnitude of A beta (1-42) inhibition is d ependent on the nAChR channel subtype expressed. Thus, chronic inhibition o f cholinergic signaling by A beta (1-42) could contribute to the cognitive deficits associated with AD.