Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J.
Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors.
J Neurochem. 2004 Apr;89(2):337-43.
PubMed.
The epidemiological evidence should now be regarded as strongly against a protective role for smoking in Alzheimer's disease. Although several early prevalence studies showed that AD was less prevalent in elderly smokers, at least one large incidence study (Rotterdam study; Ott et al., 1998) and one large follow-up study (Honolulu-Asia Aging Study; Tyas et al., 2003) have both reported that smokers have greater than twofold increases in AD risk. Another large prospective study (British doctor study; Doll et al., 2000) found a slight increase in AD risk. As argued by several authors (Riggs, 1992; Kukull, 2001; Almeida, 2002; Hill, 2003), it is likely that the prevalence studies are confounded by differential survival of smokers. The prevalence rate of a condition is dependent on both the actual occurrence of the condition and on the length of time a subject has the condition. At least one report documents that elderly smokers do have decreased survival over a five-year period (Wang et al., 1999). Smoking may affect AD risk through vascular risk factors that outweigh the benefits of nicotine.
References:
Ott A, Slooter AJ, Hofman A, van Harskamp F, Witteman JC, Van Broeckhoven C, van Duijn CM, Breteler MM.
Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study.
Lancet. 1998 Jun 20;351(9119):1840-3.
PubMed.
Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ.
Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study.
Neurobiol Aging. 2003 Jul-Aug;24(4):589-96.
PubMed.
Doll R, Peto R, Boreham J, Sutherland I.
Smoking and dementia in male British doctors: prospective study.
BMJ. 2000 Apr 22;320(7242):1097-102.
PubMed.
Riggs JE.
Cigarette smoking and Parkinson disease: the illusion of a neuroprotective effect.
Clin Neuropharmacol. 1992 Apr;15(2):88-99.
PubMed.
Kukull WA.
The association between smoking and Alzheimer's disease: effects of study design and bias.
Biol Psychiatry. 2001 Feb 1;49(3):194-9.
PubMed.
Almeida OP, Hulse GK, Lawrence D, Flicker L.
Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies.
Addiction. 2002 Jan;97(1):15-28.
PubMed.
Hill RD, Nilsson LG, Nyberg L, Bäckman L.
Cigarette smoking and cognitive performance in healthy Swedish adults.
Age Ageing. 2003 Sep;32(5):548-50.
PubMed.
Wang HX, Fratiglioni L, Frisoni GB, Viitanen M, Winblad B.
Smoking and the occurrence of Alzheimer's disease: cross-sectional and longitudinal data in a population-based study.
Am J Epidemiol. 1999 Apr 1;149(7):640-4.
PubMed.
Nicotine as a pure drug has been demonstrated to be neuroprotective in numerous in-vivo and in-vitro models. In-vitro studies indicate that the α7 subtype of nAChR mediates some types of nicotine-induced neuroprotection in cortical and hippocampal neuron cultures(1,2). α7 nAChR is a ligand-gated ion channel; receptor activation leads to net inward current and membrane depolarization. The current carried by α7 nAChRs comprises a significant fraction of calcium. Thus, α7 nAChR activation potentially influences neurotransmitter release, second messenger activity, and gene transcription. α7 nAChRs are also highly desensitizing in that prolonged exposure (seconds) to agonist causes significant receptor inactivation(3). While initially leading to transient nAChR activation, chronic exposure to nicotine will result in downregulation of receptor function.
The studies presented by the EURODERM Incidence Research Group and Jun Tan and colleagues further the notion that, while smoking is bad, nicotine is potentially good by activating neuroprotective second messenger cascades in neurons, or, based on Tan’s findings, negatively modulating the inflammatory response of microglia.
The EURODERM group convincingly demonstrates that elderly smokers and former smokers lose cognitive function more rapidly than their non-smoking counterparts. Amongst the smokers, this decline correlates with the number of cigarettes smoked per day. While we cannot parse out from this study which component(s) of a cigarette are responsible or the mechanism by which smokers’ cognitive function declines, it will be of import to determine the relative contribution of chronic nicotine exposure via effects on neuron, microglia, and astrocyte function (where several nicotinic receptor subunits are expressed) versus the contribution of inhaled tar and carbon monoxide via effects on cardiovascular function and risk of stroke.
Jun Tan and coworkers report that microglial release of TNF-α in response to LPS and other infectious challenges is attenuated by α7 nAChR stimulation. In conjunction with additional observations regarding α7 receptor distribution and function in brain, this new data sets the stage for complex cholinergic interactions between neuronal and immune cell populations mediated by the α7 nAChR. For instance, astrocytes synthesize and release acetylcholine in addition to kynurinic acid, which is a potent α7 antagonist(4). Several studies have demonstrated that astrocytes express α7 receptors as do inhibitory and excitatory neurons(5,6). In addition, the cholinergic neurons that exhibit vulnerability in several neurodegenerative diseases express this and other nicotinic receptors(7).
Based on Shytle and colleagues' findings, the cholinergic tone and inflammatory status within a particular brain region might determine whether a compensatory response is launched by the neuron, microglia, and astrocyte network, or a positive feed-back loop is set up that leads to chronic inflammation and neurodegeneration. Considering these two papers together, chronic nicotine exposure, such as that experienced by smokers’ brains, may contribute to cognitive decline by raising the net inflammatory status of the brain by desensitizing α7 nAChRs on microglia and tipping the balance between compensation and neurodegeneration.
References:
Shaw S, Bencherif M, Marrero MB.
Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid.
J Biol Chem. 2002 Nov 22;277(47):44920-4.
PubMed.
Dajas-Bailador FA, Lima PA, Wonnacott S.
The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism.
Neuropharmacology. 2000 Oct;39(13):2799-807.
PubMed.
Dani JA, Radcliffe KA, Pidoplichko VI.
Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas.
Eur J Pharmacol. 2000 Mar 30;393(1-3):31-8.
PubMed.
Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX.
The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications.
J Neurosci. 2001 Oct 1;21(19):7463-73.
PubMed.
Alkondon M, Pereira EF, Albuquerque EX.
alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices.
Brain Res. 1998 Nov 9;810(1-2):257-63.
PubMed.
Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA.
Hippocampal synaptic transmission enhanced by low concentrations of nicotine.
Nature. 1996 Oct 24;383(6602):713-6.
PubMed.
O'Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S.
The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration.
Curr Drug Targets CNS Neurol Disord. 2002 Aug;1(4):399-411.
PubMed.
Comments
Banner Sun Health Research Institute
The epidemiological evidence should now be regarded as strongly against a protective role for smoking in Alzheimer's disease. Although several early prevalence studies showed that AD was less prevalent in elderly smokers, at least one large incidence study (Rotterdam study; Ott et al., 1998) and one large follow-up study (Honolulu-Asia Aging Study; Tyas et al., 2003) have both reported that smokers have greater than twofold increases in AD risk. Another large prospective study (British doctor study; Doll et al., 2000) found a slight increase in AD risk. As argued by several authors (Riggs, 1992; Kukull, 2001; Almeida, 2002; Hill, 2003), it is likely that the prevalence studies are confounded by differential survival of smokers. The prevalence rate of a condition is dependent on both the actual occurrence of the condition and on the length of time a subject has the condition. At least one report documents that elderly smokers do have decreased survival over a five-year period (Wang et al., 1999). Smoking may affect AD risk through vascular risk factors that outweigh the benefits of nicotine.
References:
Ott A, Slooter AJ, Hofman A, van Harskamp F, Witteman JC, Van Broeckhoven C, van Duijn CM, Breteler MM. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet. 1998 Jun 20;351(9119):1840-3. PubMed.
Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2003 Jul-Aug;24(4):589-96. PubMed.
Doll R, Peto R, Boreham J, Sutherland I. Smoking and dementia in male British doctors: prospective study. BMJ. 2000 Apr 22;320(7242):1097-102. PubMed.
Riggs JE. Cigarette smoking and Parkinson disease: the illusion of a neuroprotective effect. Clin Neuropharmacol. 1992 Apr;15(2):88-99. PubMed.
Kukull WA. The association between smoking and Alzheimer's disease: effects of study design and bias. Biol Psychiatry. 2001 Feb 1;49(3):194-9. PubMed.
Almeida OP, Hulse GK, Lawrence D, Flicker L. Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies. Addiction. 2002 Jan;97(1):15-28. PubMed.
Hill RD, Nilsson LG, Nyberg L, Bäckman L. Cigarette smoking and cognitive performance in healthy Swedish adults. Age Ageing. 2003 Sep;32(5):548-50. PubMed.
Wang HX, Fratiglioni L, Frisoni GB, Viitanen M, Winblad B. Smoking and the occurrence of Alzheimer's disease: cross-sectional and longitudinal data in a population-based study. Am J Epidemiol. 1999 Apr 1;149(7):640-4. PubMed.
View all comments by Thomas BeachUniversity of Texas Medical Branch
Nicotine as a pure drug has been demonstrated to be neuroprotective in numerous in-vivo and in-vitro models. In-vitro studies indicate that the α7 subtype of nAChR mediates some types of nicotine-induced neuroprotection in cortical and hippocampal neuron cultures(1,2). α7 nAChR is a ligand-gated ion channel; receptor activation leads to net inward current and membrane depolarization. The current carried by α7 nAChRs comprises a significant fraction of calcium. Thus, α7 nAChR activation potentially influences neurotransmitter release, second messenger activity, and gene transcription. α7 nAChRs are also highly desensitizing in that prolonged exposure (seconds) to agonist causes significant receptor inactivation(3). While initially leading to transient nAChR activation, chronic exposure to nicotine will result in downregulation of receptor function.
The studies presented by the EURODERM Incidence Research Group and Jun Tan and colleagues further the notion that, while smoking is bad, nicotine is potentially good by activating neuroprotective second messenger cascades in neurons, or, based on Tan’s findings, negatively modulating the inflammatory response of microglia.
The EURODERM group convincingly demonstrates that elderly smokers and former smokers lose cognitive function more rapidly than their non-smoking counterparts. Amongst the smokers, this decline correlates with the number of cigarettes smoked per day. While we cannot parse out from this study which component(s) of a cigarette are responsible or the mechanism by which smokers’ cognitive function declines, it will be of import to determine the relative contribution of chronic nicotine exposure via effects on neuron, microglia, and astrocyte function (where several nicotinic receptor subunits are expressed) versus the contribution of inhaled tar and carbon monoxide via effects on cardiovascular function and risk of stroke.
Jun Tan and coworkers report that microglial release of TNF-α in response to LPS and other infectious challenges is attenuated by α7 nAChR stimulation. In conjunction with additional observations regarding α7 receptor distribution and function in brain, this new data sets the stage for complex cholinergic interactions between neuronal and immune cell populations mediated by the α7 nAChR. For instance, astrocytes synthesize and release acetylcholine in addition to kynurinic acid, which is a potent α7 antagonist(4). Several studies have demonstrated that astrocytes express α7 receptors as do inhibitory and excitatory neurons(5,6). In addition, the cholinergic neurons that exhibit vulnerability in several neurodegenerative diseases express this and other nicotinic receptors(7).
Based on Shytle and colleagues' findings, the cholinergic tone and inflammatory status within a particular brain region might determine whether a compensatory response is launched by the neuron, microglia, and astrocyte network, or a positive feed-back loop is set up that leads to chronic inflammation and neurodegeneration. Considering these two papers together, chronic nicotine exposure, such as that experienced by smokers’ brains, may contribute to cognitive decline by raising the net inflammatory status of the brain by desensitizing α7 nAChRs on microglia and tipping the balance between compensation and neurodegeneration.
References:
Shaw S, Bencherif M, Marrero MB. Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid. J Biol Chem. 2002 Nov 22;277(47):44920-4. PubMed.
Dajas-Bailador FA, Lima PA, Wonnacott S. The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology. 2000 Oct;39(13):2799-807. PubMed.
Dani JA, Radcliffe KA, Pidoplichko VI. Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas. Eur J Pharmacol. 2000 Mar 30;393(1-3):31-8. PubMed.
Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001 Oct 1;21(19):7463-73. PubMed.
Alkondon M, Pereira EF, Albuquerque EX. alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res. 1998 Nov 9;810(1-2):257-63. PubMed.
Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature. 1996 Oct 24;383(6602):713-6. PubMed.
O'Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S. The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Targets CNS Neurol Disord. 2002 Aug;1(4):399-411. PubMed.
View all comments by Kelly Dineley