Depletion of vitamin E increases amyloid β accumulation by decreasing its clearances from brain and blood in a mousemodel of Alzheimer disease

Yoichiro Nishida, Shingo Ito, Sumio Ohtsuki, Naoki Yamamoto, Tsubura Takahashi, Nobuhisa Iwata, Kou Ichi Jishage, Hiromi Yamada, Hiroki Sasaguri, Shigefumi Yokota, Wenying Piao, Hiroyuki Tomimitsu, Takaomi C. Saido, Katsuhiko Yanagisawa, Tetsuya Terasaki, Hidehiro Mizusawa, Takanori Yokota

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with α-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 β (Aβ) deposits in the brain, which was ameliorated with α-to-copherol supplementation. To investigate the mechanism of the increased Aβ accumulation, we here studied generation, degradation, aggregation, and efflux of Aβ in the mice. The clearance of intracerebral-microinjected 125I-Aβ 1-40 from brain was decreased in Ttpa-/- mice to be compared with wild-type mice, whereas the generation of Aβ was not increased in Ttpa-/-APPsw mice. The activity of an Aβ-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa-/- mouse brain. In contrast, Aβ aggregation was accelerated in Ttpa-/- mouse brains compared with wild-type brains, and well known molecules involved in Aβ 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 125I-Aβ1-40 was decreased in Ttpa-/- mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of α-tocopherol impairs Aβ clearances from the brain and from the blood, possibly causing increased Aβ accumulation in Ttpa-/- APPsw mouse brain and plasma.

Original languageEnglish
Pages (from-to)33400-33408
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number48
DOIs
Publication statusPublished - 2009 Nov 27

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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