Abstract
Recent studies have reported that the cholinergic anti-inflammatory pathway regulates peripheral inflammatory responses via alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and that acetylcholine and nicotine regulate the expression of proinflammatory mediators such as TNF-alpha and prostaglandin E2 in microglial cultures. In a previous study we showed that ATP released by beta-amyloid-stimulated microglia induced reactive oxygen species (ROS) production, in a process involving the P2X(7) receptor (P2X(7)R), in an autocrine fashion. These observations led us to investigate whether stimulation by nicotine could regulate fibrillar beta amyloid peptide (1-42) (fAbeta1-42)-induced ROS production by modulating ATP efflux-mediated Ca(2+) influx through P2X(7)R. Nicotine inhibited ROS generation in fAbeta(1-42)-stimulated microglial cells, and this inhibition was blocked by mecamylamine, a non-selective nAChR antagonist, and a-bungarotoxin, a selective alpha7 nAChR antagonist. Nicotine inhibited NADPH oxidase activation and completely blocked Ca(2+) influx in fAbeta(1-42)-stimulated microglia. Moreover, ATP release from fAbeta(1-42)-stimulated microglia was significantly suppressed by nicotine treatment. In contrast, nicotine did not inhibit 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP)-induced Ca(2+) influx, but inhibited ROS generation in BzATP-stimulated microglia, indicating an inhibitory effect of nicotine on a signaling process downstream of P2X(7)R. Taken together, these results suggest that the inhibitory effect of nicotine on ROS production in fAbeta1-42-stimulated microglia is mediated by indirect blockage of ATP release and by directly altering the signaling process downstream from P2X(7)R.
Highlights
The neuropathological hallmarks of Alzheimer’s disease (AD) include extracellular deposition of the beta amyloid peptide (Aβ) in the form of senile plaques and the appearance of intracellular neurofibrillary tangles composed of hyperphosphorylated tau (Akiyama et al, 2000)
We examined the effects of nicotine on reactive oxygen species (ROS) production in fAβ1-42-stimulated microglia by measuring fluorescence signals from dihydrodichlorofluorescein diacetate (DCF-DA)
Nicotine significantly decreased DCF fluorescence signals, in a dosedependent manner (Figure 1). These results indicated that neuroprotective functions of nicotine might be mediated by suppressing fAβ1-42-induced ROS production in microglia
Summary
The neuropathological hallmarks of Alzheimer’s disease (AD) include extracellular deposition of the beta amyloid peptide (Aβ) in the form of senile plaques and the appearance of intracellular neurofibrillary tangles composed of hyperphosphorylated tau (Akiyama et al, 2000). Another neuropathological feature of AD is the loss of both cholinergic neurons (Davies and Maloney, 1976; McGeer et al, 1984; Muir, 1997) and nicotinic acetylcholine receptors (nAChRs) (Burghaus et al, 2000; Mousavi et al, 2003) in the basal forebrain, which contributes to cognitive dysfunction. The administration of nAChR agonists in aging animals and humans induced cognitive improvement (Newhouse et al, 1997; Terry and Buccafuso, 2003) and prevented neuronal death induced by Aβ (O'Neill et al, 2002).
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