title: Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling.
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.
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, USA.
authors.forename: Natasa
authors.initials: N
authors.lastname: Dragicevic
authors.forename: Neil
authors.initials: N
authors.lastname: Copes
authors.forename: Gina
authors.initials: G
authors.lastname: O'Neal-Moffitt
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
authors.forename: Robert
authors.initials: R
authors.lastname: Buzzeo
authors.forename: Maggie
authors.initials: M
authors.lastname: Mamcarz
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.forename: James M
authors.initials: JM
authors.lastname: Olcese
authors.forename: Gary W
authors.initials: GW
authors.lastname: Arendash
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Bradshaw
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D007211:Indoles / Q000494:pharmacology; D007735:Kynuramine / Q000031:analogs & derivatives / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma; D011422:Propionates / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044094:Receptors, Melatonin / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D016564:Amyloid beta-Protein Precursor; D007211:Indoles; D011422:Propionates; D017382:Reactive Oxygen Species; D044094:Receptors, Melatonin; D007735:Kynuramine; C041550:N-acetyl-N-formyl-5-methoxykynurenamine; D000255:Adenosine Triphosphate; C095446:3-(indol-3-yl)propionic acid; D008550:Melatonin