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J. Biol. Chem., Vol. 279, Issue 47, 49523-49532, November 19, 2004

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Tumor Necrosis Factor-, Interleukin-1, and Interferon- Stimulate -Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway^*

Yung-Feng Liao, Bo-Jeng Wang, Hui-Ting Cheng, Lan-Hsin Kuo, and Michael S. Wolfe¶||

From the Laboratory of Molecular Neurobiology, Institute of Zoology, Academia Sinica, Taipei 115, Taiwan and the ^¶Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

The deposition of the amyloid (A) peptide in neuritic plaques plays a critical role in the pathogenesis of Alzheimer's disease (AD). A is generated through the proteolysis of amyloid precursor protein (APP) by the sequential actions of - and -secretases. Although recent evidence has unveiled much about the biochemical identity and characteristics of -secretase, the mechanism regulating endogenous -secretase activity remains elusive. To identify possible extracellular signals and associated signaling cascades that could regulate APP proteolysis by -secretase activity, we have developed a cell-based reporter gene assay by stably cotransfecting HEK293 cells with the Gal4-driven luciferase reporter gene and the Gal4/VP16-tagged C-terminal fragment of APP (C99-GV), the immediate substrate of -secretase. The cleavage of C99-GV by -secretase releases the transcription factor that activates luciferase expression, providing a quantitative measurement of -secretase activity. Using this reporter assay, we have demonstrated that interferon-, interleukin-1, and tumor necrosis factor- can specifically stimulate -secretase activity, concomitant with increased production of A and the intracellular domain of APP (AICD). The -secretase-dependent cleavage of Notch is also enhanced upon the stimulation of these cytokines. The cytokine-enhanced -secretase activity can be suppressed by a potent inhibitor of c-Jun N-terminal kinase (JNK). Furthermore, cells transfected with dominant-positive MEKK1, one of the most potent activators of the JNK cascade, exhibit increased -secretase activity, suggesting that the JNK-dependent mitogen-activated protein kinase pathway could mediate the cytokine-elicited regulation of -secretase. Our studies provide direct evidence that cytokine-elicited signaling cascades control A production by modulating -secretase activity.

Received for publication, February 24, 2004 , and in revised form, September 1, 2004.

^* This work was supported in part by National Science Council, Taiwan, Grants NSC 92-2320-B-001-046 and NSC 93-3112-B-001-015 and Academia Sinica (to Y.-F. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Supported by the National Institutes of Health and the Alzheimer's Association.

To whom correspondence should be addressed: Institute of Zoology, Rm. 328, Academia Sinica, 128 Sec. 2 Academia Rd., Taipei, 115, Taiwan. Tel.: 886-2-27899535; Fax: 886-2-27858059; E-mail: yliao{at}sinica.edu.tw.

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