Depletion of vitamin E increases amyloid β accumulation by decreasing its clearances from brain and blood in a mousemodel 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 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. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.