Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease |
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| Authors: | James M. Olcese Chuanhai Cao Takashi Mori Malgorzata B. Mamcarz Anne Maxwell Melissa J. Runfeldt Li Wang Chi Zhang Xiaoyang Lin Guixin Zhang Gary W. Arendash |
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| Affiliation: | Florida State University College of Medicine, Tallahassee, FL;;Byrd Alzheimer's Center and Research Institute, Tampa, FL;;Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL;;Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, USA;;Departments of Medical Science and Pathology, Saitama Medical Center/University, Saitama, Japan;;The Florida Alzheimer's Disease Research Center, Tampa, FL, USA |
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| Abstract: | Abstract: The neurohormone melatonin has been reported to exert anti-β-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 β-amyloid (Aβ) 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 Aβ deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Aβ1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Aβ levels were elevated. These Aβ results, together with our concurrent demonstration that melatonin suppresses Aβ aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Aβ from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-α 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-Aβ 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. |
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| Keywords: | Alzheimer disease β-amyloid cytokines melatonin memory oxidative stress transgenic mice |
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