title: 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.
abstract: OBJECTIVE
  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-β 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 Aβ production and degradation in neuronal cell lines.
  
  
  METHODS
  Beside amyloid-β level the mechanisms leading to Aβ production and degradation are examined.
  
  
  RESULTS
  Surprisingly, all tocopherols have shown to increase Aβ level by enhancing the Aβ production and decreasing the Aβ degradation. Aβ production is enhanced by an elevated activity of the involved enzymes, the β- 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 Aβ production, δ-tocopherol showed the highest potency to increase Aβ generation. Beside Aβ production, Aβ clearance was decreased by affecting IDE, one of the major Aβ 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-β 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.
authors.affiliation: Marcus Grimm, Kirrberger Str.1, Building 90.1, 66421 Homburg/Saar, Germany; Tel: +49-6841-1647919; Fax: +49-6841-1624137; E-mail: Marcus.Grimm@uks.eu.
authors.forename: M O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: C P
authors.initials: CP
authors.lastname: Stahlmann
authors.forename: J
authors.initials: J
authors.lastname: Mett
authors.forename: V J
authors.initials: VJ
authors.lastname: Haupenthal
authors.forename: V C
authors.initials: VC
authors.lastname: Zimmer
authors.forename: J
authors.initials: J
authors.lastname: Lehmann
authors.forename: B
authors.initials: B
authors.lastname: Hundsdörfer
authors.forename: K
authors.initials: K
authors.lastname: Endres
authors.forename: H S
authors.initials: HS
authors.lastname: Grimm
authors.forename: T
authors.initials: T
authors.lastname: Hartmann
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D000686:Amyloidosis / Q000139:chemically induced; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D007339:Insulysin / Q000378:metabolism; D015227:Lipid Peroxidation; D009447:Neuroblastoma / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D024505:Tocopherols / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D024504:gamma-Tocopherol; D053829:Amyloid Precursor Protein Secretases; D007339:Insulysin; D024502:alpha-Tocopherol; C479072:delta-tocopherol; D024505:Tocopherols