Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling
Article first published online: 1 MAR 2011
© 2011 John Wiley & Sons A/S
Journal of Pineal Research
Volume 51, Issue 1, pages 75–86, August 2011
How to Cite
Dragicevic, N., Copes, N., O’Neal-Moffitt, G., Jin, J., Buzzeo, R., Mamcarz, M., Tan, J., Cao, C., Olcese, J. M., Arendash, G. W. and Bradshaw, P. C. (2011), Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling. Journal of Pineal Research, 51: 75–86. doi: 10.1111/j.1600-079X.2011.00864.x
- Issue published online: 13 JUL 2011
- Article first published online: 1 MAR 2011
- Accepted manuscript online: 1 FEB 2011 09:37AM EST
- Received October 22, 2010; accepted January 12, 2011.
- melatonin receptor;
- indole-3-propionic acid;
Abstract: Mitochondrial dysfunction is a hallmark of Alzheimer’s disease (AD) and is observed in mutant amyloid precursor protein (APP) transgenic mouse models of familial AD. Melatonin is a potent antioxidant, can prevent toxic aggregation of Alzheimer’s beta-amyloid (Aβ) peptide and, when taken long term, can protect against cognitive deficits in APP transgenic mice. To study the effects of melatonin on brain mitochondrial function in an AD model, APP/PS1 transgenic mice were treated for 1 month with melatonin. Analysis of isolated brain mitochondria from mice indicated that melatonin treatment decreased mitochondrial Aβ levels by two- to fourfold in different brain regions. This was accompanied by a near complete restoration of mitochondrial respiratory rates, membrane potential, and ATP levels in isolated mitochondria from the hippocampus, cortex, or striatum. When isolated mitochondria from untreated young mice were given melatonin, a slight increase in respiratory rate was observed. No such effect was observed in mitochondria from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. This restoration was partially blocked by melatonin receptor antagonists indicating melatonin receptor signaling is required for the full effect. Therefore, treatments that stimulate melatonin receptor signaling may be beneficial for restoring mitochondrial function in AD, and preservation of mitochondrial function may an important mechanism by which long term melatonin treatment delays cognitive dysfunction in AD mice.