Cerebral Palsy

Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). We previously crossed AD transgenic (APPsw) model mice with alpha-tocopherol transfer protein knockout (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 (alpha-Toc) 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 intracerebrally microinjected [125I]Abeta1-40 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 (IDE) was markedly decreased in Ttpa-/- mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa-/- mouse brains compared with wild-type ones, 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 upregulated in the small vascular fraction of Ttpa-/- mouse brains. Moreover, disappearance of intravenously administered [125I]Abeta1-40 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-Toc impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa-/-APPsw mouse brain and plasma.