β-Amyloid Peptide Activates Non-α7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons

Abstract

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.

Amyloid β Protein Modulates Glutamate-Mediated Neurotransmission in the Rat Basal Forebrain: Involvement of Presynaptic Neuronal Nicotinic Acetylcholine and Metabotropic Glutamate Receptors

“…A number of electrophysiological studies, in a variety of in vitro preparations, have demonstrated that A␤ 1-42 can exert its effects through both ␣7 and ␣4␤2 nAChRs (Pettit et al, 2001;Dineley et al, 2002;Fu and Jhamandas, 2003;Wu et al, 2004;Lamb et al, 2005). However, the precise nature of A␤ 1-42 interactions with nAChRs is controversial because some studies have reported that A␤ 1-42 activates nAChRs (Dineley et al, 2002;Fu and Jhamandas, 2003), whereas other studies suggested that A␤ 1-42 inhibits nAChRs (Pettit et al, 2001;Wu et al, 2004;Lamb et al, 2005). Both ␣7 and non-␣7 subtypes of nAChRs were reported to be involved in such A␤-mediated interactions.…”

“…The A␤ 1-42 -mediated increase in mEPSC frequency is antagonized by the nAChR antagonist dihydro-␤-erythroidine but not ␣-bungarotoxin Because A␤ 1-42 has been found to have high affinity to nAChRs and to be capable of influencing the function of these receptors (Wang et al, 2000a;Pettit et al, 2001;Fu and Jhamandas, 2003), we used dihydro-␤-erythroidine (DH␤E) (a selective ␣4␤2 nAChR antagonist) and ␣-bungarotoxin (a selective non-␣7 nAChR antagonist) to investigate the possible receptor subtypes involved in the A␤ 1-42 -mediated change in mEPSC frequency. We first tested the effect of DH␤E on the A␤ 1-42 -mediated increase in mEPSCs in identified cholinergic neurons.…”

“…However, binding studies using postmortem human brain tissue and ␣7SK-N-MC cell membranes indicate that A␤ shows a high affinity for neuronal nicotinic acetylcholine receptors (nAChRs) (Wang et al, 2000a,b). Furthermore, electrophysiological studies in Xenopus oocytes (Dineley et al, 2002) and rat neurons (Pettit et al, 2001;Fu and Jhamandas, 2003) demonstrate that effects of A␤ are expressed through a variety of subtypes of nAChRs. Although there are very few examples of primary nicotinic-mediated excitatory synaptic transmission in the CNS (Phelan and Gallagher, 1992;Zhang et al, 1993;Frazier et al, 1998), nAChRs have been demonstrated to be involved as neuromodulators of glutamate-mediated excitatory synaptic transmission (Vidal and Changeux, 1993;McGehee et al, 1995;Alkondon et al, 1996;Radcliffe and Dani, 1998;Lambe et al, 2003).…”

Cotinine Inhibits Amyloid-β Peptide Neurotoxicity and Oligomerization

“…Mecamylamine, at a concentration that inhibited nAChRs in cultured brain cells [7], and block nicotine's neuroprotective activity [12], did not affect cotinine neuroprotective activity. This evidence strongly suggests that cotinine triggers neuroprotective mechanisms distinctive from nicotine.…”

“…Pretreatment with mecamylamine (1 µM), a dose that inhibits nAChRs in cultured brain cells [7], did not affect the neuroprotective activity of cotinine and the increase in neuronal survival (p > 0.05) (Figure1B).…”