Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology

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.