Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by beta-amyloid1-42 peptide.
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 beta-amyloid (Abeta1-42) peptide; however, the link between Abeta1-42 and the loss of cognitive function has not been established. Many groups have shown direct interactions between Abeta1-42 and nAChR function, however, with differing results. For example, in rat hippocampal CA1 interneurons in slices, we found that Abeta1-42 inhibits nAChR channels directly, and non-alpha7 receptors were more sensitive to block than alpha7 receptors. However, some groups have found that alpha7 subtypes were potently blocked by Abeta1-42, whereas other groups reported that Abeta1-42 can activate nAChRs (i.e., both alpha7 and non-alpha7 subtypes). To further investigate the link between nAChR function and Abeta1-42, we expressed various subtypes of nAChRs in Xenopus oocytes (e.g., alpha4beta2, alpha2beta2, alpha4alpha5beta2, and alpha7) and found that Abeta1-42 blocked these various non-alpha7 nAChRs, without any effect on alpha7 nAChRs. Furthermore, none of these channels was activated by Abeta1-42. The relative block by Abeta1-42 was dependent on the subunit makeup and apparent stoichiometry of these receptors. These data further support our previous findings that Abeta1-42 directly and preferentially inhibits non-alpha7 nAChRs.
Lamb
Patricia W
PW
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709 <f.
Melton
Mark A
MA
Yakel
Jerrel L
JL
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020033:Protein Isoforms; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42)