title: Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease.
abstract: 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.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519. Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Shingo
authors.initials: S
authors.lastname: Ito
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tsubura
authors.initials: T
authors.lastname: Takahashi
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Kou-Ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yamada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yokota
authors.forename: Wenying
authors.initials: W
authors.lastname: Piao
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomimitsu
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024505:Tocopherols / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein; D053829:Amyloid Precursor Protein Secretases; D024502:alpha-Tocopherol; D024505:Tocopherols
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