Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases

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Abstract

Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the α4 (but not α3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not α-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Aβ1–42, but not related to plaque or tangle densities. In contrast, α-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of α4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased α4 immunoreactivity in the cortex and lower densities of amyloid-β plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the α4 subunit in β-amyloidosis but not in nigro-striatal dopaminergic degeneration.

Introduction

Research on the role of neuronal nicotinic receptors in brain ageing and degenerative diseases associated with ageing such as Alzheimer's disease and dementia with Lewy bodies, Parkinson's disease, aims to determine:

1. Which nicotinic receptors subtypes are affected and how the receptor is involved in pathological changes such as system degeneration and neuron loss, β-amyloidosis, abnormal tau, Lewy body and Lewy neurite formation.

2. What is the evidence that any particular subtype contributes to the pathological cascade and that receptor modification will thus protect against the development of, e.g. Alzheimer's and Parkinson's diseases.

3. How receptor abnormalities are linked to specific clinical symptoms and what are the prospects for receptor-targeted symptomatic therapy.

The loss of nicotinic receptors with increasing age is one of the most consistent findings in relation to changes in the ageing human brain. Changes in the cortex or hippocampus from maturity to old age include: reductions in nicotine binding (likely to reflect α4 or α3); α-bungarotoxin binding (α7); and α3, α4 and β2 mRNA Flynn and Mash, 1986, Perry et al., 1986, Schröder, et al., 1991, Court et al., 1992, Nordberg et al., 1992, Court et al., 1997, Terzano et al., 1998, Tohgi et al., 1998a, Tohgi et al., 1998b, Utsugisawa et al., 1999. In the striatum a reduction in nicotine binding occurs only after the age of 75 years (Hellström-Lindahl and Court, in press), contrasting with the cortex and hippocampus where the receptor declines earlier. These differential patterns of age-related changes may reflect functional changes in mnemonic function (associated with the hippocampus) occurring earlier during normal ageing than in extrapyramidal motor dysfunction.

The further changes that take place in Alzheimer's and Parkinson's disease include the loss of high affinity agonist (nicotine, cytisidine or epibatidine) binding which occurs in the cortex in both diseases and also in the striatum in Parkinson's disease Perry et al., 1995, Warpman and Nordberg 1995, Clementi et al., 1999. In Alzheimer's disease, loss of cortical epibatidine binding is related to decreased synaptophysin immunoreactivity (Sabbagh et al., 1998). Immunochemical evidence (Martin-Ruiz et al., 1999) indicates that the loss of cortical receptor binding in Alzheimer's disease reflects changes in α4 but not α3 or α7 subunits and a preliminary immunohistochemical analysis has identified the loss of both α4 and β2 reactive fibres (Sparks et al., 1998).

The present investigation includes alterations in nicotinic receptors in Alzheimer's disease examined in relation to clinical and pathological indices of disease severity and in view of an emerging strong correlation with acetylcholinesterase, also nicotinic receptor changes in a transgenic mouse model over expressing acetylcholinesterase Beeri et al., 1995, Beeri et al., 1997. Comparisons are made between Parkinson's disease and Dementia with Lewy bodies and evidence of an early involvement of nicotinic receptors in substantia nigra dopaminergic neuronal degeneration are examined. Potentially protective effects of nicotinic receptor modulation on pathological features of Alzheimer's disease (cortical plaques and tangles) and Parkinson's disease (substantia nigra neuron loss) are also examined in the brains of normal elderly individuals (in which these features occur to a lesser extent with increasing age) chronically exposed to nicotine (tobacco smokers). The hypothesis that nicotinic receptors are centrally involved in the pathological cascade and clinical symptomatology in both Alzheimer and Lewy body diseases is thus explored.

Section snippets

Cases

Newcastle series. Cases of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies, together with age matched controls, were selected according to previously published clinical and pathological diagnostic criteria Perry et al., 1990, Perry et al., 1995, Martin-Ruiz et al., 1999, McKeith et al., 1996. Also included is a series of middle aged to elderly normal individuals with an established history of tobacco use (aged-matched smokers and non-smokers), described in detail

Alzheimer's disease

Fig. 1 illustrates levels of nicotine and α-bungarotoxin binding in regions of the hippocampus and entorhinal cortex in age matched Alzheimer's disease and control cases from the Newcastle series. Nicotine binding was reduced to some extent in all areas, and significantly in stratum lacunosum and entorhinal cortex. In contrast, there were no significant differences in α-bungarotoxin binding between Alzheimer's disease and controls. Although there appeared in this same series to be a relation

DISCUSSION

In relation to the questions posed in the Section 1, the data described support the following conclusions:

1. Although there is a generalised loss of different nicotinic receptors subtypes in aging, nicotinic receptor loss in the cortex in Alzheimer's disease selectively involves the subtype containing the α4 subunit, but not α3 or α7, whereas the striatal receptor loss in Parkinson's disease reflects a subunit other than α3, α4 or α6.

2. The receptor loss in Alzheimer's disease is more closely

Acknowledgements

Thanks to Chris Morris for genotyping, the EU for TMR funding (CMM), Dawn Houghton and Lorraine Hood for manuscript preparation.

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