Protective effect of melatonin on soluble Aβ1-42-induced memory impairment, astrogliosis, and synaptic dysfunction via the Musashi1/Notch1/Hes1 signaling pathway in the rat hippocampus

Alzheimers Res Ther. 2016 Sep 15;8(1):40. doi: 10.1186/s13195-016-0206-x.


Background: Amyloid-beta (Aβ) plays a key role in Alzheimer's disease (AD) pathogenesis, and soluble Aβ oligomers are more cytotoxic than Aβ fibrils. Recent evidence suggests that Notch signaling is affected by AD and other brain diseases. Melatonin exerts beneficial effects on many aspects of AD and may protect against myocardial ischemia via Notch1 signaling regulation. Therefore, we hypothesized that the Notch1 signaling pathway is involved in the neuroprotective role of melatonin against soluble Aβ1-42.

Methods: An AD rat model was established via repeated intracerebroventricular administration of soluble Aβ1-42. Melatonin treatment was administered 24 hours prior to Aβ1-42 administration via an intraperitoneal injection. The effects of melatonin on spatial learning and memory, synaptic plasticity, and astrogliosis were investigated. The expression of several Notch1 signaling components, including Notch1, the Notch1 intracellular domain (NICD), Hairy and enhancer of split 1 (Hes1, a downstream effector of Notch), and Musashi1 (a positive regulator of Notch), were examined using immunohistochemistry, western blotting, and quantitative real-time PCR. In vitro studies were conducted to determine whether the melatonin-mediated protection against Aβ1-42 was inhibited by DAPT, an inhibitor of Notch signaling.

Results: Melatonin improved the Aβ1-42-induced impairment in spatial learning and memory, attenuated synaptic dysfunction, and reduced astrogliosis. Melatonin also ameliorated the effects of Aβ1-42 on Notch1, NICD, Hes1, and Musashi1. The in vitro studies demonstrated that DAPT effectively blocked the neuroprotective effect of melatonin against Aβ1-42.

Conclusions: These findings suggest that melatonin may improve the soluble Aβ1-42-induced impairment of spatial learning and memory, synaptic plasticity, and astrogliosis via the Musashi1/Notch1/Hes1 signaling pathway.

Keywords: Hes1; Learning and memory; Melatonin; Musashi1; Neuroplasticity; Notch1; Soluble Aβ1–42.

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Behavior, Animal
  • Disease Models, Animal
  • Gliosis / drug therapy*
  • Hippocampus / drug effects*
  • Male
  • Melatonin / administration & dosage
  • Melatonin / pharmacology*
  • Memory Disorders / chemically induced
  • Memory Disorders / drug therapy*
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / drug effects*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / toxicity*
  • RNA-Binding Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Notch1 / drug effects
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / drug effects*
  • Spatial Learning / drug effects*
  • Transcription Factor HES-1 / metabolism


  • Amyloid beta-Peptides
  • Hes1 protein, rat
  • Msi1 protein, rat
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Notch1 protein, rat
  • Peptide Fragments
  • RNA-Binding Proteins
  • Receptor, Notch1
  • Transcription Factor HES-1
  • amyloid beta-protein (1-42)
  • Melatonin