Vitamin E: Curse or Benefit in Alzheimer's Disease? A Systematic Investigation of the Impact of α-, γ- and δ-Tocopherol on Aß Generation and Degradation in Neuroblastoma Cells.

OBJECTIVES: 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-ß 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 Aß production and degradation in neuronal cell lines. MEASUREMENTS: Beside amyloid-ß level the mechanisms leading to Aß production and degradation are examined. RESULTS: Surprisingly, all tocopherols have shown to increase Aß level by enhancing the Aß production and decreasing the Aß degradation. Aß production is enhanced by an elevated activity of the involved enzymes, the ß- 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 α-tocopherol had only minor effects on Aß production, δ-tocopherol showed the highest potency to increase Aß generation. Beside Aß production, Aß clearance was decreased by affecting IDE, one of the major Aß degrading enzymes. CONCLUSIONS: 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-ß 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.

Altered membrane fluidity and lipid raft composition in presenilin-deficient cells.

The pathology of Alzheimer's disease is closely connected with lipid metabolism. Processing of amyloid precursor protein (APP) is sensitive to membrane alterations in levels of cholesterol and gangliosides. As cholesterol and gangliosides are major components of rafts and BACE I and gamma-secretase are supposed to be localized to rafts there might be a yet unknown biological function underlying this connection. Increasing evidence shows a close connection between cholesterol homeostasis and APP processing and Abeta production respectively. We measured membrane fluidity by anisotropy determination, isolated detergent resistant membrane (DRM) fractions from membrane preparations and determined cholesterol content of these fractions by a coupled enzymatic assay. We found membrane fluidity to be changed in mouse embryonic fibroblasts (MEF) PS1/2 -/- along with altered cholesterol content in DRM fraction of these cells. In addition, total ganglioside levels were enhanced in absence of presenilin (PS).