Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease

J Pineal Res. 2009 Aug;47(1):82-96. doi: 10.1111/j.1600-079X.2009.00692.x. Epub 2009 Jun 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / blood
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Catalase / biosynthesis
  • Catalase / genetics
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Cognition Disorders / prevention & control*
  • Disease Models, Animal
  • Glutathione Peroxidase / biosynthesis
  • Glutathione Peroxidase / genetics
  • Maze Learning / drug effects
  • Melatonin / pharmacology*
  • Memory / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oxidoreductases / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics


  • Amyloid beta-Peptides
  • RNA, Messenger
  • Oxidoreductases
  • Catalase
  • Glutathione Peroxidase
  • Superoxide Dismutase
  • Melatonin