Thromboxane receptor activation mediates isoprostane-induced increases in amyloid pathology in Tg2576 mice

被引:30
作者
Shineman, Diana W. [1 ,2 ]
Zhang, Bin [1 ,2 ]
Leight, Susan N. [1 ,2 ]
Pratico, Domenico [3 ]
Lee, Virginia M. -Y. [1 ,2 ]
机构
[1] Univ Penn, Sch Med, Dept Pathol, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Lab Med, Philadelphia, PA 19104 USA
[3] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19122 USA
关键词
Alzheimer's disease; amyloid-beta; APP; lipid peroxidation; isoprostane; thromboxane receptor;
D O I
10.1523/JNEUROSCI.0684-08.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alzheimer's disease (AD) amyloid plaques are composed of amyloid-beta(A beta) peptides produced from proteolytic cleavage of amyloid precursor protein (APP). Isoprostanes, markers of in vivo oxidative stress, are elevated in AD patients and in the Tg2576 mouse model of AD-like A beta brain pathology. To determine whether isoprostanes increase A beta production, we delivered isoprostane iPF(2 alpha)-III into the brains of Tg2576 mice. Although treated mice showed increased brain A beta levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF(2 alpha)-III on A beta. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased A beta and secreted APP ectodomains. This increase was a result of increased APP mRNA stability leading to elevated APP mRNA and protein levels. The increased APP provides more substrate for alpha and beta secretase proteolytic cleavages, thereby increasing A beta generation and amyloid plaque deposition. To test the effectiveness of targeting the TP receptor for AD therapy, Tg2576 mice underwent long-term treatment with S18886, an orally available TP receptor antagonist. S18886 treatment reduced amyloid plaques, insoluble A beta, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.
引用
收藏
页码:4785 / 4794
页数:10
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