Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 48, Pages 33400-33408Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.054056
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Funding
- Ministry of Health, Labor, and Welfare of Japan
- 21st Century COE Program on Brain Integration and Its Disorders
- Ministry of Education, Science, and Culture
- Japan Science and Technology Agency
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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 (A beta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased A beta accumulation, we here studied generation, degradation, aggregation, and efflux of A beta in the mice. The clearance of intracerebral-microinjected I-125-A beta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wildtype mice, whereas the generation of A beta was not increased in Ttpa(-/-) APPsw mice. The activity of an A beta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, A beta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in A beta 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 I-125-A beta(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 A beta clearances from the brain and from the blood, possibly causing increased A beta accumulation in Ttpa(-/-) APPsw mouse brain and plasma.
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