Nicotine and neurodegeneration in ageing

doi:10.1016/S0378-4274(01)00502-1

Toxicology Letters

Volume 127, Issues 1–3, 28 February 2002, Pages 207-215

https://doi.org/10.1016/S0378-4274(01)00502-1 Get rights and content

Abstract

Impairment in cholinergic systems is a highly consistent finding in human dementia. Among cholinergic markers, marked decreases in nicotine binding have been most consistently observed in the telencephalic regions of demented patients and are thought to contribute to the cognitive deficits associated with ageing and age-related neurodegenerative diseases. New evidence that the cholinergic system has a specific pathogenic role in the neurodegenerative alterations of aged and, especially, demented patients is fast accumulating. Both in vivo and in culture, nicotine protects striatal, hippocampal and cortical neurons against the neurotoxicity induced by excitotoxic amino acids as well as the toxicity caused by β-amyloid, the major component of senile plaques. Further support for the implication of nicotinic receptors in brain ageing is come from recent studies on transgenic animals lacking nicotinic receptor subtypes, which shed light on the mechanisms of nicotine neuroprotection and neurotoxicity.

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, GABA_A 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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Review articleNicotine and neurodegeneration in ageing

Abstract

Introduction

Section snippets

Diversity of nAChRs in the CNS

Smoking and incidence of age-related neurodegenerative diseases

In vivo and in vitro evidence for nAChR-related neurotoxicity and neuroprotection

Conclusions

Acknowledgments

Behav. Brain Res.

Neuropharmacology

Brain Res. Rev.

Brain Res.

Behav. Brain Res.

Behav. Brain Res.

Eur. J. Pharmacol.

Brain Res.

Prog. Neurobiol.

Behav. Brain Res.

Brain Res.

Jpn. J. Pharmacol.

Neurobiol. Learn. Mem.

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res. Rev.

Review article
Nicotine and neurodegeneration in ageing