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Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by β-amyloid1–42 peptide

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Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in a variety of physiological processes, including cognition and development. Dysfunctions in nAChRs have been linked to Alzheimer’s disease (AD), a human neurological disorder that is the leading cause of dementia. AD is characterized by an increasing loss of cognitive function, nAChRs, cholinergic neurons, and choline acetyltransferase activity. A major hallmark of AD is the presence of extracellular neuritic plaques composed of the β-amyloid (Aβ1–42) peptide; however, the link between Aβ1–42 and the loss of cognitive function has not been established. Many groups have shown direct interactions between Aβ1–42 and nAChR function, however, with differing results. For example, in rat hippocampal CA1 interneurons in slices, we found that Aβ1–42 inhibits nAChR channels directly, and non-α7 receptors were more sensitive to block than α7 receptors. However, some groups have found that α7 subtypes were potently blocked by Aβ1–42, whereas other groups reported that Aβ1–42 can activate nAChRs (i.e., both α7 and non-α7 subtypes). To further investigate the link between nAChR function and Aβ1–42, we expressed various subtypes of nAChRs in Xenopus oocytes (e.g., α4β2, α2β2, α4α5β2, and α7) and found that Aβ1–42 blocked these various non-α7 nAChRs, without any effect on α7 nAChRs. Furthermore, none of these channels was activated by Aβ1–42. The relative block by Aβ1–42 was dependent on the subunit makeup and apparent stoichiometry of these receptors. These data further support our previous findings that Aβ1–42 directly and preferentially inhibits non-α7 nAChRs.

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Correspondence to Jerrel L. Yakel.

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Lamb, P.W., Melton, M.A. & Yakel, J.L. Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by β-amyloid1–42 peptide. J Mol Neurosci 27, 13–21 (2005). https://doi.org/10.1385/JMN:27:1:013

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