Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease

J Pineal Res. 2004 Sep;37(2):129-36. doi: 10.1111/j.1600-079X.2004.00144.x.


Melatonin is an endogenous antioxidant and free radical scavenger. A transgenic (Tg) mouse model for Alzheimer's disease mimics the accumulation of senile plaques, neuronal apoptosis and memory impairment. Previous studies indicated that melatonin reduced beta-amyloid (Abeta)-induced neurotoxicity. In this study, after giving melatonin at 10 mg/kg to APP 695 transgenic (APP 695 Tg) mice for 4 months, we evaluated the long-term influence of melatonin on behavior, biochemical and neuropathologic changes in APP 695 Tg mice. Step-down and step-through passive avoidance tests suggested that 8-month-old APP 695 Tg mice showed decreases in step-down latency and step-through latency and increases in count of error throughout the entire learning trial and memory session, which suggested learning and memory impairment. However, melatonin alleviated learning and memory deficits. Additionally, choline acetyltransferase (ChAT) activity also decreased in the frontal cortex and hippocampus of APP 695 Tg mice compared with non-Tg littermates. Melatonin supplementation increased ChAT activity in the frontal cortex and hippocampus. DNA fragmentation was present in the frontal cortex of the APP 695 Tg mice; melatonin reduced the number of apoptotic neurons. Congo Red staining and Bielschowsky silver impregnation both showed the apparent extracellular Abeta deposition in frontal cortex of APP 695 Tg mice. However, melatonin decreased the Abeta deposits. Our results indicate that neuroprotection by melatonin is partly related to modulation of apoptosis and protection of the cholinergic system. Early rational melatonin interventions may be one of the most promising strategies in the development of approaches to retard or prevent Abeta-mediated disease progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / enzymology
  • Brain / pathology*
  • Choline O-Acetyltransferase / drug effects
  • Choline O-Acetyltransferase / metabolism
  • Cholinergic Fibers / drug effects
  • Cholinergic Fibers / pathology
  • Disease Models, Animal
  • In Situ Nick-End Labeling
  • Learning / drug effects
  • Melatonin / therapeutic use*
  • Memory / drug effects
  • Mice
  • Mice, Transgenic
  • Neuroprotective Agents / therapeutic use*


  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Choline O-Acetyltransferase
  • Melatonin