Loss of nicotinic acetylcholine receptor subunits α4 and α7 in the cerebral cortex of Parkinson patients

doi:10.1016/S1353-8020(03)00028-2

Parkinsonism & Related Disorders

Volume 9, Issue 5, June 2003, Pages 243-246

https://doi.org/10.1016/S1353-8020(03)00028-2 Get rights and content

Abstract

Cerebral cortical cholinergic deficits, represented by a decrease in choline acetyltransferase activity, severe losses of nicotinic binding sites as well as cell degeneration in the basal forebrain can be observed in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The potential role of nicotinic acetylcholine receptor subunits as pharmacological targets for the treatment of cognitive deficits raises the question as to what extent these subunits are affected in neurodegenerative diseases. We here report on a significant decrease of the α4 and the α7 nicotinic acetylcholine receptor subunit in cortices of Parkinson patients which turns out to be similar to recent findings in Alzheimer patients.

Introduction

Patients suffering from Parkinson's disease (PD) have repeatedly been shown to develop deficits of the cholinergic system. In particular at the subcortical level a marked degeneration and loss of magnocellular cholinergic neurons in the basal nucleus of Meynert, and at the cortical level a reduction of choline acetyltransferase (ChAT) activity and a massive decrease of nicotinic binding sites have been described [1], [2], [3], [4]. In summary, these findings are similar to deficits of cholinergic neurotransmission that also can be found in Alzheimer's disease (AD) [5], [6].

The search for potential targets for a treatment of neurodegenerative diseases associated with cholinergic deficits has led to an increasing interest in nicotinic acetylcholine receptors (nAChR). The number of the different nAChR subunits and their possible combinations forming different receptor subtypes may explain the individual anatomical distribution, the electrophysiological and pharmacological diversity as well as the variable effects of nAChR agonists and antagonists. The most frequent nAChRs in the central nervous system (CNS) are composed of two α4 and three β2 subunits. They represent approximately 90% of the high affinity binding sites for nicotine and ACh [7]. Recently, α4 and α7 nAChR subunit proteins have been shown to be markedly decreased in frontal and temporal cortices of AD patients [8], [9], [10], [11]. At present no quantitative data are available on nAChR protein expression in PD. Therefore, we performed a Western blotting investigation on the α4 and α7 nAChR isoforms in PD as compared to age-matched controls.

Section snippets

Materials

Autopsy samples of human cerebral cortex (superior temporal gyrus) from five individuals (three males, two females, age range: 57–78, mean: 66±8) with a neuropathologically proven diagnosis of PD were compared with tissue samples of five individuals (three males, two females, age range: 53–75, mean: 67±9) with no neurological history or neuropathological findings at autopsy and histopathological examination. Cortical samples were obtained from the Institut für Neuropathologie (Referenzzentrum

α4 nAChR expression

In Western blots, mAb 299 showed a single immunoreactive signal at 70 kDa. As shown in Table 1 and Fig. 1, Fig. 3, in PD the detected signals were clearly decreased by approximately 29%. Comparing the values obtained for the non-PD individuals with those of the PD patients, the differences observed were shown to be statistically significant (p<0.05).

α7 nAChR expression

MAb 306 showed a single immunoreactive signal at 58 kDa. The expression showed marked differences when comparing both groups studied (Table 1, Fig.

Discussion

Among other pathologic deficits of the CNS, impairment of central cholinergic transmission has been shown to be an important feature of neurodegenerative diseases such as PD and AD. Several studies have provided evidence for a loss of cortical nicotinic receptor proteins, which plays an important role in the cognitive deficits observed clinically in these diseases [19], [20], [21], [22], [23]. Recently, the α4 and α7 subunits have been shown to be decreased in several cortical areas in AD in

Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (H.S.) (Schr 283/18-3), the Köln Fortune Program, Faculty of Medicine, University of Cologne (L.B.) and the Fonds der Chemischen Industrie (FCI) (H.S.).

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Loss of nicotinic acetylcholine receptor subunits α4 and α7 in the cerebral cortex of Parkinson patients

Abstract

Introduction

Section snippets

Materials

α4 nAChR expression

α7 nAChR expression

Discussion

Acknowledgements

Neuroscience

Eur J Pharmacol

Prog Neurobiol

Mol Brain Res

Neurobiol Dis

Neuron

J Neuroimmunol

Anal Biochem

Neurosci Lett

Biol Psychiatry

Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

J Neurochem

A postmortem study of brain nicotinic receptors in Parkinson's and Alzheimer's disease

Brain Res