title: Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex.
abstract: Alteration by beta-amyloid (Abeta) of signaling via nicotinic acetylcholine receptors (nAChRs) has been implicated in the early stages of Alzheimer's disease. nAChRs function both post- and presynaptically in the nervous system; however, little is known about the functional consequence of the interaction of Abeta with these receptors, particularly those on presynaptic nerve terminals. In view of the strong correlation between loss of synaptic terminals and dementia, together with the reduction in nAChRs in Alzheimer's disease, the possibility exists that presynaptic nAChRs may be targets for Abeta. To explore this possibility, we assessed the effect of Abeta peptides on nicotine-evoked changes in presynaptic Ca2+ level via confocal imaging of isolated presynaptic nerve endings from rat hippocampus and neocortex. Abeta1-42 appeared to inhibit presynaptic nAChR activation by nicotine. Surprisingly, picomolar Abeta1-42 was found to directly evoke sustained increases in presynaptic Ca2+ via nAChRs, revealing that the apparent inhibitory action of Abeta1-42 was the result of an occlusion of nicotine to further stimulate the receptors. The direct effect of Abeta was found to be sensitive to alpha-bungarotoxin, mecamylamine, and dihydro-beta-erythroidine, indicating involvement of alpha7-containing nAChRs and non-alpha7-containing nAChRs. Prior depolarization strongly attenuated subsequent Abeta-evoked responses in a manner dependent on the amplitude of the initial presynaptic Ca2+ increase, suggesting that nerve activity or Ca2+ channel density may control the impact of Abeta on presynaptic nerve terminal function. Together, these results suggest that the sustained increases in presynaptic Ca2+ evoked by Abeta may underlie disruptions in neuronal signaling via nAChRs in the early stages of Alzheimer's disease.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dougherty
authors.forename: Jianlin
authors.initials: J
authors.lastname: Wu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nichols
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D019579:Neocortex / Q000737:chemistry / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); C092395:amyloid beta-protein (12-28); D009538:Nicotine; D002118:Calcium