Vitamin E: Curse or benefit in Alzheimer's disease? A systematic investigation of the impact of [alpha]-, [gamma]- and [delta]-tocopherol on A[beta] generation and degradation in neuroblastoma cells

The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-[beta] production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on A[beta] production and degradation in neuronal cell lines. Beside amyloid-[beta] level the mechanisms leading to A[beta] production and degradation are examined. Surprisingly, all tocopherols have shown to increase A[beta] level by enhancing the A[beta] production and decreasing the A[beta] degradation. A[beta] production is enhanced by an elevated activity of the involved enzymes, the [beta]- and γ-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas [alpha]-tocopherol had only minor effects on A[beta] production, δ-tocopherol showed the highest potency to increase A[beta] generation. Beside A[beta] production, A[beta] clearance was decreased by affecting IDE, one of the major A[beta] degrading enzymes. Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-[beta] level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential.