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The Journal of Neuroscience, April 30, 2008, 28(18):4785-4794; doi:10.1523/JNEUROSCI.0684-08.2008

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Neurobiology of Disease
Thromboxane Receptor Activation Mediates Isoprostane-Induced Increases in Amyloid Pathology in Tg2576 Mice

Diana W. Shineman,¹ Bin Zhang,¹ Susan N. Leight,¹ Domenico Pratico,² and Virginia M.-Y. Lee¹

¹Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ²Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122

Correspondence should be addressed to Virginia M.-Y. Lee, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Maloney Building, 3rd Floor, 3600 Spruce Street, Philadelphia, PA 19104-4283. Email: vmylee{at}mail.med.upenn.edu

Alzheimer's disease (AD) amyloid plaques are composed of amyloid-β (Aβ) 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 Aβ brain pathology. To determine whether isoprostanes increase Aβ production, we delivered isoprostane iPF₂-III into the brains of Tg2576 mice. Although treated mice showed increased brain Aβ levels and plaque-like deposits, this was blocked by a thromboxane (TP) receptor antagonist, suggesting that TP receptor activation mediates the effects of iPF₂-III on Aβ. This hypothesis was supported by cell culture studies that showed that TP receptor activation increased Aβ 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 and β secretase proteolytic cleavages, thereby increasing Aβ 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 Aβ, and APP levels, thereby implicating TP receptor signaling as a novel target for AD therapy.

Key words: Alzheimer's disease; amyloid-β; APP; lipid peroxidation; isoprostane; thromboxane receptor

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Received Feb. 14, 2008; revised March 21, 2008; accepted March 26, 2008.

Correspondence should be addressed to Virginia M.-Y. Lee, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Maloney Building, 3rd Floor, 3600 Spruce Street, Philadelphia, PA 19104-4283. Email: vmylee{at}mail.med.upenn.edu

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