Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology.
BACKGROUND
Calcium (Ca2+) 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 Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD).


RESULTS
Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca2+-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 beta-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures.


CONCLUSIONS
These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.
Cao
Xia
X
The Cell Signalling Laboratory, Neuropsychiatry Research Unit, University of Saskatchewan, 103 Wiggins Road, Saskatoon, SK S7N 5E4, Canada. caoxia25@hotmail.com
Wei
Zelan
Z
Gabriel
Geraldine G
GG
Li
XinMin
X
Mousseau
Darrell D
DD
D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005609:Free Radicals / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010545:Peroxides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005609:Free Radicals; D010545:Peroxides; D008995:Monoamine Oxidase; D002118:Calcium