Inhibition of Alzheimer β-fibrillogenesis by melatonin

It is generally postulated that the amyloid beta protein (A beta) plays a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathologic properties of this protein, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of A beta to form beta-sheet structures or amyloid fibrils. We report that melatonin, a hormone recently found to protect neurons against A beta toxicity, interacts with A beta 1-40 and A beta 1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. These interactions between melatonin and the amyloid peptides were demonstrated by circular dichroism and electron microscopy for A beta 1-40 and A beta 1-42 and by nuclear magnetic resonance spectroscopy for A beta 1-40. Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.