title: Prophylactic melatonin significantly reduces Alzheimer's neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPP(swe)/PS1 mice.
abstract: BACKGROUND
  Alzheimer's disease (AD) underlies dementia for millions of people worldwide, and its occurrence is set to double in the next 20 years. Currently, approved drugs for treating AD only marginally ameliorate cognitive deficits, and provide limited symptomatic relief, while newer substances under therapeutic development are potentially years away from benefiting patients. Melatonin (MEL) for insomnia has been proven safe with >15 years of over-the-counter access in the US. MEL exerts multiple complementary mechanisms of action against AD in animal models; thus it may be an excellent disease-modifying therapeutic. While presumed to provide neuroprotection via activation of known G-protein-coupled melatonin receptors (MTNRs), some data indicate MEL acts intracellularly to protect mitochondria and neurons by scavenging reactive oxygen species and reducing free radical formation. We examined whether genetic deletion of MTNRs abolishes MEL's neuroprotective actions in the AβPP(swe)/PSEN1dE9 mouse model of AD (2xAD). Beginning at 4 months of age, both AD and control mice either with or without both MTNRs were administered either MEL or vehicle in drinking water for 12 months.
  
  
  RESULTS
  Behavioral and cognitive assessments of 15-month-old AD mice revealed receptor-dependent effects of MEL on spatial learning and memory (Barnes maze, Morris Water Maze), but receptor-independent neuroprotective actions of MEL on non-spatial cognitive performance (Novel Object Recognition Test). Similarly, amyloid plaque loads in hippocampus and frontal cortex, as well as plasma Aβ1-42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL's efficacy in reducing cortical antioxidant gene expression (Catalase, SOD1, Glutathione Peroxidase-1, Nrf2) only when receptors were present. Increased cytochrome c oxidase activity was seen in 16 mo AD mice as compared to non-AD control mice. This increase was completely prevented by MEL treatment of 2xAD/MTNR+ mice, but only partially prevented in 2xAD/MTNR- mice, consistent with mixed receptor-dependent and independent effects of MEL on this measure of mitochondrial function.
  
  
  CONCLUSIONS
  These findings demonstrate that prophylactic MEL significantly reduces AD neuropathology and associated cognitive deficits in a manner that is independent of antioxidant pathways. Future identification of direct molecular targets for MEL action in the brain should open new vistas for development of better AD therapeutics.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University Program in Neuroscience, 1115 West Call Street, Tallahassee, FL, 32306, USA. gmoffitt@neuro.fsu.edu.
authors.forename: G
authors.initials: G
authors.lastname: O'Neal-Moffitt
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL, 33620, USA. delic2@mail.usf.edu.
authors.forename: V
authors.initials: V
authors.lastname: Delic
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL, 33620, USA. pbradsha@usf.edu.
authors.forename: P C
authors.initials: PC
authors.lastname: Bradshaw
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Florida State University Program in Neuroscience, 1115 West Call Street, Tallahassee, FL, 32306, USA. james.olcese@med.fsu.edu.
authors.forename: J
authors.initials: J
authors.lastname: Olcese
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000097:blood; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000235:genetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005106:Exploratory Behavior; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning; D008550:Melatonin / Q000627:therapeutic use*; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000097:blood; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D044094:Receptors, Melatonin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D044094:Receptors, Melatonin; C000606290:SOD1 protein, human; C075222:amyloid beta-protein (1-42); D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008550:Melatonin; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse