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J. Biol. Chem., Vol. 281, Issue 24, 16419-16427, June 16, 2006

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ADAM10 Activation Is Required for Green Tea (–)-Epigallocatechin-3-gallate-induced -Secretase Cleavage of Amyloid Precursor Protein^*

Demian F. Obregon¹, Kavon Rezai-Zadeh¹, Yun Bai, Nan Sun, Huayan Hou, Jared Ehrhart, Jin Zeng, Takashi Mori, Gary W. Arendash^¶, Doug Shytle^||, Terrence Town^**2, and Jun Tan^||3

From the Neuroimmunology Laboratory, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, ^¶The Byrd Alzheimer's Center and Research Institute, Tampa, Florida 33647, the ^||Center for Excellence in Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, Florida 33613, the Institute of Medical Science, Saitama Medical School, Saitama 350-8550, Japan, and the ^**Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519

Recently, we have shown that green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain A levels, resulting in mitigation of cerebral amyloidosis in a mouse model of Alzheimer disease. EGCG seems to accomplish this by modulating amyloid precursor protein (APP) processing, resulting in enhanced cleavage of the -COOH-terminal fragment (-CTF) of APP and corresponding elevation of the NH₂-terminal APP product, soluble APP- (sAPP-). These beneficial effects were associated with increased -secretase cleavage activity, but no significant alteration in -or -secretase activities. To gain insight into the molecular mechanism whereby EGCG modulates APP processing, we evaluated the involvement of three candidate-secretase enzymes, a-disintegrin and metalloprotease (ADAM) 9, 10, or 17, in EGCG-induced non-amyloidogenic APP metabolism. Results show that EGCG treatment of N2a cells stably transfected with "Swedish" mutant human APP (SweAPP N2a cells) leads to markedly elevated active (60 kDa mature form) ADAM10 protein. Elevation of active ADAM10 correlates with increased -CTF cleavage, and elevated sAPP-. To specifically test the contribution of ADAM10 to non-amyloidogenic APP metabolism, small interfering RNA knockdown of ADAM9, -10, or -17 mRNA was employed. Results show that ADAM10 (but not ADAM9 or -17) is critical for EGCG-mediated -secretase cleavage activity. In summary, ADAM10 activation is necessary for EGCG promotion of non-amyloidogenic (-secretase cleavage) APP processing. Thus, ADAM10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease.

Received for publication, January 20, 2006 , and in revised form, April 17, 2006.

^* This work was supported in part by grants from the Institute for the Study of Aging (to J. T.) and the Johnnie B. Byrd Senior Alzheimer's Center and Research Institute (to J. T. and D. S.). 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.

¹ Both authors contributed equally to this work.

² Supported by a Ruth L. Kirschstein National Institutes of Health/National Research Service Award/National Institute of Aging postdoctoral fellowship and an Alzheimer Association grant.

³ To whom correspondence should be addressed: Neuroimmunology Laboratory, Silver Child Development Center, Dept. of Psychiatry and Behavioral Medicine, College of Medicine, University of South Florida. 3515 E. Fletcher Ave., Tampa, FL 33613. Tel.: 813-974-9326; Fax: 813-974-1130; E-mail: jtan{at}hsc.usf.edu.

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