Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Aβ peptide

Inheritance of apoE4 is a strong risk factor for the development of late-onset sporadic Alzheimer's disease (AD). Several lines of evidence suggest that apoE4 binds to the Alzheimer A beta protein and, under certain experimental conditions, promotes formation of beta -sheet structures and amyloid fibrils. Deposition of amyloid fibrils is a critical step in the development of AD. We report here that addition of melatonin to A beta in the presence of apoE resulted in a potent isoform-specific inhibition of fibril formation, the extent of which was far greater than that of the inhibition produced by melatonin alone. This effect was structure-dependent and unrelated to the antioxidant properties of melatonin, since it could be reproduced neither with the structurally related indole N-acetyl-5-hydroxytryptamine nor with the antioxidants ascorbate, alpha -tocophenol, and PBN. The enhanced inhibitory effects of melatonin and apoE were lost when bovine serum albumin was substituted for apoE. In addition, A beta in combination with apoE was highly neurotoxic (apoE4 > apoE3) to neuronal cells in culture, and this activity was also prevented by melatonin. These findings suggest that reductions in brain melatonin, which occur during aging, may contribute to a proamyloidogenic microenvironment in the aging brain.