Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease

J Biol Chem. 2009 Nov 27;284(48):33400-8. doi: 10.1074/jbc.M109.054056. Epub 2009 Aug 13.


Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation, and efflux of Abeta in the mice. The clearance of intracerebral-microinjected (125)I-Abeta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa(-/-)APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in Abeta transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa(-/-) mouse brains. Moreover, the disappearance of intravenously administered (125)I-Abeta(1-40) was decreased in Ttpa(-/-) mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-tocopherol impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa(-/-)APPsw mouse brain and plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / blood
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / pharmacokinetics
  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Blotting, Northern
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Dietary Supplements
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Tocopherols / metabolism*
  • alpha-Tocopherol / administration & dosage
  • alpha-Tocopherol / pharmacology


  • Amyloid beta-Peptides
  • Carrier Proteins
  • alpha-tocopherol transfer protein
  • Amyloid Precursor Protein Secretases
  • alpha-Tocopherol
  • Tocopherols