Obregon Demian F, Rezai-Zadeh Kavon, Bai Yun, Sun Nan, Hou Huayan, Ehrhart Jared, Zeng Jin, Mori Takashi, Arendash Gary W, Shytle Doug, Town Terrence, Tan Jun
Neuroimmunology Laboratory, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, The Byrd Alzheimer's Center and Research Institute, 3515 E. Fletcher Avenue, Tampa, FL 33647, USA.
J Biol Chem. 2006 Jun 16;281(24):16419-27. doi: 10.1074/jbc.M600617200. Epub 2006 Apr 19.
Recently, we have shown that green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain Abeta 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 alpha-COOH-terminal fragment (alpha-CTF) of APP and corresponding elevation of the NH(2)-terminal APP product, soluble APP-alpha (sAPP-alpha). These beneficial effects were associated with increased alpha-secretase cleavage activity, but no significant alteration in beta-or gamma-secretase activities. To gain insight into the molecular mechanism whereby EGCG modulates APP processing, we evaluated the involvement of three candidate alpha-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 ( approximately 60 kDa mature form) ADAM10 protein. Elevation of active ADAM10 correlates with increased alpha-CTF cleavage, and elevated sAPP-alpha. 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 alpha-secretase cleavage activity. In summary, ADAM10 activation is necessary for EGCG promotion of non-amyloidogenic (alpha-secretase cleavage) APP processing. Thus, ADAM10 represents an important pharmacotherapeutic target for the treatment of cerebral amyloidosis in Alzheimer disease.
最近，我们已经表明，绿茶多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG）在降低大脑β-淀粉样蛋白水平方面发挥有益作用，从而减轻阿尔茨海默病小鼠模型中的脑淀粉样变性。EGCG似乎通过调节淀粉样前体蛋白（APP）的加工来实现这一点，导致APP的α-羧基末端片段（α-CTF）的切割增强以及氨基末端APP产物可溶性APP-α（sAPP-α）相应升高。这些有益作用与α-分泌酶切割活性增加有关，但β-或γ-分泌酶活性无明显改变。为了深入了解EGCG调节APP加工的分子机制，我们评估了三种候选α-分泌酶，即a-解整合素和金属蛋白酶（ADAM）9、10或17在EGCG诱导的非淀粉样生成性APP代谢中的作用。结果表明，用“瑞典”突变型人APP稳定转染的N2a细胞（SweAPP N2a细胞）经EGCG处理后，活性（约60 kDa成熟形式）ADAM10蛋白显著升高。活性ADAM10的升高与α-CTF切割增加以及sAPP-α升高相关。为了特异性测试ADAM10对非淀粉样生成性APP代谢的贡献，采用了小干扰RNA敲低ADAM9、-10或-17的mRNA。结果表明，ADAM10（而非ADAM9或-17）对EGCG介导的α-分泌酶切割活性至关重要。总之，ADAM10激活是EGCG促进非淀粉样生成性（α-分泌酶切割）APP加工所必需的。因此，ADAM10是治疗阿尔茨海默病脑淀粉样变性的重要药物治疗靶点。
