A peptide derived from acetylcholinesterase induces neuronal cell death: characterisation of possible mechanisms.
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.
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010455:Peptides; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D014810:Vitamin E; D007770:L-Lactate Dehydrogenase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000110:Acetylcholinesterase; D020169:Caspases; D008550:Melatonin