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The Journal of Neuroscience, November 12, 2008, 28(46):12052-12061; doi:10.1523/JNEUROSCI.2913-08.2008

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Neurobiology of Disease
Effects of TNF-Converting Enzyme Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo

Minkyu L. Kim,¹ Bin Zhang,¹ Ian P. Mills,¹ Marcos E. Milla,² Kurt R. Brunden,¹ and Virginia M.-Y. Lee¹

¹Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ²In Vitro Pharmacology–Inflammation Discovery, Roche Pharmaceuticals, Palo Alto, California 94304

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

Tumor necrosis factor- (TNF) is a proinflammatory cytokine that is elevated in Alzheimer's disease (AD) brains. Because TNF is released from cell membranes by the TNF-converting enzyme (TACE), inhibition of TACE has the potential to mitigate TNF effects in AD brain. TACE also cleaves amyloid precursor protein (APP) and generates sAPP, precluding the formation of potentially harmful amyloid β (Aβ) peptides by β-site APP cleaving enzymes (BACE). Hence, the anti-inflammatory benefits of TACE inhibition might be offset by an increase in Aβ. We have examined the effects of the highly selective TACE inhibitor, BMS-561392, on APP processing in vitro and in vivo. In Chinese hamster ovary cells expressing APP, BMS-561392 significantly reduced secretion of sAPP without a corresponding increase in Aβ production. Conversely, a BACE inhibitor decreased sAPPβ and Aβ peptides with no change in the secretion of sAPP. These data indicate an absence of TACE and BACE competition for the APP substrate. Despite this, we observed competition for APP when TACE activity was enhanced via phorbol ester treatment or if APP was modified such that it was retained within the trans-Golgi network (TGN). These results suggest that BACE and TACE share a common TGN localization, but under normal conditions do not compete for APP. To confirm this finding in vivo, BMS-561392 was infused into the brains of Tg2576 and wild-type mice. Although decreased brain sAPP levels were observed, steady-state Aβ levels were not significantly changed. Accordingly, it is possible that TACE inhibitors could reduce TNF levels without increasing Aβ levels within the AD brain.

Key words: Alzheimer's disease; amyloid-β; inflammation; neuroinflammation; tumor necrosis factor; TNF

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Received June 24, 2008; revised Aug. 21, 2008; accepted Oct. 5, 2008.

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

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