Beta-amyloid peptide activates non-alpha7 nicotinic acetylcholine receptors in rat basal forebrain neurons.
Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by profound deficits in memory and cognitive function. Neuropathological hallmarks of the disease include a loss of basal forebrain cholinergic neurons and the deposition of beta-amyloid peptide (Abeta) in neuritic plaques. At a cellular level, considerable attention has focused on a study of Abeta interactions with the neuronal nicotinic acetylcholine receptor (nAChR) subtypes. In this study, using cell-attached and outside-out single channel recordings from acutely dissociated rat basal forebrain neurons, we report that Abeta and nicotine activate nAChRs with two distinct levels of single-channel conductance. Whole cell recordings from these neurons reveal Abeta and nicotine, in a concentration-dependent and reversible manner, evoke brisk depolarizing responses and an inward current. The effects of Abeta on both single channel and whole cell are blocked by the noncompetitive nAChR antagonist mecamylamine and competitive nAChR antagonist dihydro-beta-erythroidine, but not the specific alpha7-selective nAChR antagonist methyllycaconitine, indicating that Abeta activated non-alpha7 nAChRs on basal forebrain neurons. In addition, the non-alpha7 nAChR agonists UB-165, epibatidine, and cytisine, but not the selective alpha7 agonist AR-R17779, induced similar responses as Abeta and nicotine. Thus non-alpha7 nAChRs may also represent a novel target in mediating the effects of Abeta in AD.
Fu
Wen
W
Department of Medicine, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Jhamandas
Jack H
JH
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579165:Chrna7 protein, rat; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35)