title: ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein.
abstract: 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.
authors.affiliation: 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.
authors.forename: Demian F
authors.initials: DF
authors.lastname: Obregon
authors.forename: Kavon
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Nan
authors.initials: N
authors.lastname: Sun
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Gary W
authors.initials: GW
authors.lastname: Arendash
authors.forename: Doug
authors.initials: D
authors.lastname: Shytle
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002392:Catechin / Q000031:analogs & derivatives* / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D013662:Tea
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D034741:RNA, Small Interfering; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse