title: Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease.
abstract: The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.
authors.affiliation: Florida State University College of Medicine, Tallahassee, FL, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Olcese
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Malgorzata B
authors.initials: MB
authors.lastname: Mamcarz
authors.forename: Anne
authors.initials: A
authors.lastname: Maxwell
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Runfeldt
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Lin
authors.forename: Guixin
authors.initials: G
authors.lastname: Zhang
authors.forename: Gary W
authors.initials: GW
authors.lastname: Arendash
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics; D003072:Cognition Disorders / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D010088:Oxidoreductases; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D008550:Melatonin