QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Shineman, D. W. Articles by Lee, V. M.-Y. Search for Related Content PubMed PubMed Citation Articles by Shineman, D. W. Articles by Lee, V. M.-Y.

 Previous Article  |  Next Article 

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

---

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

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2008 28: i. [Full Text]  

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help