title: Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer's mice and cells.
abstract: Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APP(sw) showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A(2a) and A₁ adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APP(sw) transgenic mouse and cell models of Alzheimer's disease.
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 E. Fowler Ave., ISA 2015, Tampa, FL 33620, USA.
authors.forename: Natasa
authors.initials: N
authors.lastname: Dragicevic
authors.forename: Vedad
authors.initials: V
authors.lastname: Delic
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.forename: Neil
authors.initials: N
authors.lastname: Copes
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Lin
authors.forename: Maggie
authors.initials: M
authors.lastname: Mamcarz
authors.forename: Li
authors.initials: L
authors.lastname: Wang
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 / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D066298:In Vitro Techniques; D008550:Melatonin / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects*; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D000697:Central Nervous System Stimulants; D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D002110:Caffeine; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D008550:Melatonin