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Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex
Journal article   Open access   Peer reviewed

Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex

John J Dougherty, Jianlin Wu and Robert A Nichols
The Journal of neuroscience, v 23(17), pp 6740-6747
30 Jul 2003
DOI: https://doi.org/10.1523/JNEUROSCI.23-17-06740.2003
PMID: 12890766
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.jneurosci.org/content/jneuro/23/17/6740.full.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1523/JNEUROSCI.23-17-06740.2003View
Published, Version of Record (VoR) Open

Abstract

alpha7 Nicotinic Acetylcholine Receptor Amyloid beta-Peptides - pharmacology Animals Calcium - metabolism Corpus Striatum - chemistry Corpus Striatum - metabolism Hippocampus - chemistry Hippocampus - metabolism Male Neocortex - chemistry Neocortex - metabolism Nicotine - pharmacology Nicotinic Antagonists - pharmacology Peptide Fragments - pharmacology Presynaptic Terminals - chemistry Presynaptic Terminals - metabolism Rats Rats, Sprague-Dawley Receptors, Nicotinic - drug effects Receptors, Nicotinic - metabolism Synaptosomes - chemistry Synaptosomes - drug effects Synaptosomes - metabolism
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.

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