Amyloid-β neurotoxicity in organotypic culture is attenuated by melatonin: involvement of GSK-3β, tau and neuroinflammation

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid-beta (A beta) peptide in brain regions that are important for memory and cognition. The buildup of A beta aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against A beta-induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 mu m of A beta(25-35) in the absence or in the presence of melatonin (25, 50, or 100 mu m). In addition, the authors have investigated the involvement of GSK-3 beta, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against A beta-induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to A beta(25-35). In addition, melatonin significantly reduced the activation of GSK-3 beta, the phosphorylation of tau protein, the glial activation and the A beta-induced increase of TNF-alpha and IL-6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating A beta-induced phosphorylation of tau protein, and preventing GSK-3 beta activation and neuroinflammation.