Review articleNicotine and neurodegeneration in ageing
Introduction
Nicotine is a major component of tobacco and is thought to be the principal substance responsible for tobacco dependence. Besides its addictive action, nicotine and its analogs exert a number of effects on the central nervous system (CNS), which depend on the activation of specific receptor molecules called nicotinic acetylcholine receptors (nAChRs). nAChRs are physiologically gated by the endogenous neurotransmitter acetylcholine. Cholinergic neurons are present in both the peripheral nervous system and CNS. In mammals, peripheral cholinergic motoneurons are responsible for neurotransmission at the level of the neuromuscular junction and the autonomic ganglia, where nAChRs are the principal receptors mediating synaptic transmission. In addition, cholinergic neuronal systems are present in several regions of the CNS, including the basal telencephalic nuclei, the dorsal pontine nuclei and the medial habenula (Zoli, 2000). Activation of nAChRs in these pathways has a number of effects, including potentiation of cognitive functions, psychomotor stimulation, reinforcement and analgesia.
This paper will focus on a particular action of central nAChRs, i.e. their role in neurodegeneration. After a brief description of some main structural and functional characteristics of nAChRs, we will review the studies that link nicotine and nAChRs to human age-related neurodegenerative diseases and then the in vivo and in vitro evidence for nAChR-related neurotoxicity and neuroprotection.
Section snippets
Diversity of nAChRs in the CNS
nAChRs belong to a superfamily of ligand-gated ion channels, which comprise nicotinic acetylcholine, glycine, GABAA γ-aminobutyric and 5HT3 serotonin receptors (Le Novère and Changeux, 1995, Changeux et al., 1998). nAChRs are pentameric cationic channels, whose subunits are encoded by at least 16 distinct genes, with tissue-specific expression pattern. nAChR subunits are conventionally distinguished into α subunits, which contain some crucial amino acids responsible for acetylcholine binding,
Smoking and incidence of age-related neurodegenerative diseases
First, indirect, evidence linking nAChRs and age-related neurodegenerative diseases comes from epidemiological studies on smoking, Parkinson's disease (PD) and Alzheimer's disease (AD). Several studies have shown that a negative association exists between cigarette smoking and PD or AD, so that non-smokers have about twice PD or AD risk than smokers (Fratiglioni and Wang, 2000). However, this association is more consistently found for PD than for AD, especially when possible biases, such as
In vivo and in vitro evidence for nAChR-related neurotoxicity and neuroprotection
While the human studies discussed above suggest the existence of a link between nAChRs and age-related neurodegenerative diseases, there is growing evidence obtained in animal models that the cholinergic system, and specifically activation of nAChRs, has direct effects on neurodegeneration. These studies suggest that nAChRs have a specific pathogenic role in the development of the neuropathological lesions present in ageing and age-related neurodegenerative diseases.
Structural markers of brain
Conclusions
Overall, a series of studies point to a neuroprotective action of nAChRs. Although the molecular mechanisms of this effect are presently unknown, nAChR activation may have an important role in neuron survival during senescence and its loss may contribute to neuronal loss observed in ageing and age-related neurodegenerative diseases.
Acknowledgments
This work was supported by a grant from Italian Telethon.
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