Abstract
BackgroundAmyloid-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.MethodsAn 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.ResultsMelatonin 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.ConclusionsThese 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.
Highlights
Amyloid-beta (Aβ) plays a key role in Alzheimer’s disease (AD) pathogenesis, and soluble Aβ1–42 group (Aβ) oligomers are more cytotoxic than Aβ fibrils
We initially investigated whether melatonin prevented the spatial learning and memory impairments induced by repeated soluble Aβ1–42 i.c.v. injections using the Morris Water Maze (MWM) test
These findings suggest that the melatonin treatment prevented the soluble Aβ1–42-induced impairment in spatial learning
Summary
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. We hypothesized that the Notch signaling pathway is involved in the neuroprotective role of melatonin against soluble Aβ1–42. Aβ1–42 accumulation in the brain plays a crucial role in AD pathogenesis and has been proposed as a trigger for AD onset and progression [2, 3]. Over the previous 15 years, substantial evidence has suggested that soluble Aβ oligomers (AβOs) play pivotal roles in the synaptic dysfunction, neurodegeneration, neuroinflammation, and cognitive deficits present in AD [4, 5]. AβOs are attractive targets for therapeutics and diagnostics because of their early and unifying pathological appearance [5,6,7]
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