BioMed Central Page 1 of 10 (page number not for citation purposes) BMC Neuroscience Open Access Research article Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology Xia Cao, Zelan Wei, Geraldine G Gabriel, XinMin Li and Darrell D Mousseau* Address: The Cell Signalling Laboratory, Neuropsychiatry Research Unit, University of Saskatchewan, 103 Wiggins Road, Saskatoon, SK S7N 5E4, Canada Email: Xia Cao - caoxia25@hotmail.com; Zelan Wei - zew422@mail.usask.ca; Geraldine G Gabriel - ggg658@mail.usask.ca; XinMin Li - xin- min.li@usask.ca; Darrell D Mousseau* - darrell.mousseau@usask.ca * Corresponding author Abstract Background: Calcium (Ca 2+ ) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca 2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD). Results: Incubation with Ca 2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca 2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca 2+ -binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation) associated with either A23187 or the AD-related β-amyloid peptide, which also increases free intracellular Ca 2+ , is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures. Conclusion: These data suggest that increases in intracellular Ca 2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress. Background MAO-A and MAO-B, two isoforms of monoamine oxidase (MAO), are expressed on the mitochondrial outer mem- brane. MAO-mediated neurodegeneration can result from the formation of hydrogen peroxide (H 2 O 2 ) as a by-prod- uct of metabolism of aminergic neurotransmitters includ- ing serotonin and dopamine. If it is not detoxified by antioxidant systems such as glutathione peroxidase – one of the most abundant such systems in brain [1] – then H 2 O 2 can be converted by iron-mediated Fenton reactions to hydroxyl radicals that can initiate lipid peroxidation and cell death. This is exacerbated when antioxidant sys- tems are compromised, such as during aging [2]. The reduction in the efficacy of these systems may simply be Published: 16 September 2007 BMC Neuroscience 2007, 8:73 doi:10.1186/1471-2202-8-73 Received: 12 May 2007 Accepted: 16 September 2007 This article is available from: http://www.biomedcentral.com/1471-2202/8/73 © 2007 Cao et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.