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A peptide derived from acetylcholinesterase induces neuronal cell death: characterisation of possible mechanisms

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Abstract

Acetylcholinesterase (AChE) exhibits functions unrelated to the catalysis of acetylcholine (ACh) in particular during development. Although the underlying mechanism(s) is presently unknown, a candidate peptide fragment (AChE-peptide) has recently been identified, and been shown to induce a continuum of apoptotic and necrotic neuronal cell death in rat hippocampal organotypic cultures. The aim of this study was to trace the cell death pathway initiated by AChE-peptide. Using specific antagonists, it was possible to track a series of cellular events following application of 1 nM AChE-peptide: NMDA receptor activation, opening of the L-type voltage gated calcium channel, activation of calcium/calmodulin kinase II, generation of reactive oxygen species and caspase activation. Pharmacological interception at any stage of this cascade blocked the effect of 1 nM AChE-peptide on neurite retraction. Lactate dehydrogenase (LDH) release, a marker for cell lysis, was unaffected by 1 nM AChE-peptide. In contrast, cell death induced by 1 mM AChE-peptide, monitored as neurite retraction and increased LDH efflux, was not offset by any drug treatment. These data suggest that nanomolar concentrations of AChE-peptide exhibit pathophysiological activity via an apoptotic pathway that could play an important role in neuronal development and neurodegeneration.

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Acknowledgements

We thank Synaptica Ltd. (Oxford, UK) for support, Dr Steven Butcher for helpful comments, and Kevin Pryor for technical assistance.

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  1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

    T. Day & S. A. Greenfield

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  1. T. Day
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Correspondence to S. A. Greenfield.

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Day, T., Greenfield, S.A. A peptide derived from acetylcholinesterase induces neuronal cell death: characterisation of possible mechanisms. Exp Brain Res 153, 334–342 (2003). https://doi.org/10.1007/s00221-003-1567-5

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