title: Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.
abstract: Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-β (Aβ) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aβ generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aβ-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aβ levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.
authors: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America ; Department of Neurology, Shanghai Changhai Hospital, Shanghai, China.
authors: She-Qing
authors: SQ
authors: Zhang
authors: Darrell
authors: D
authors: Sawmiller
authors: Song
authors: S
authors: Li
authors: Kavon
authors: K
authors: Rezai-Zadeh
authors: Huayan
authors: H
authors: Hou
authors: Shufeng
authors: S
authors: Zhou
authors: Douglas
authors: D
authors: Shytle
authors: Brian
authors: B
authors: Giunta
authors: Frank
authors: F
authors: Fernandez
authors: Takashi
authors: T
authors: Mori
authors: Jun
authors: J
authors: Tan
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; C016627:octyl gallate; D005707:Gallic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
references: J Neurosci. 2005 Sep 21;25(38):8807-14
references: 16177050
references: Nature. 1999 Dec 2;402(6761):533-7
references: 10591213
references: FASEB J. 2003 May;17(8):952-4
references: 12670874
references: Curr Med Chem. 2002 Jun;9(11):1107-19
references: 12052175
references: J Clin Invest. 2004 May;113(10):1456-64
references: 15146243
references: Science. 2002 Jul 19;297(5580):353-6
references: 12130773
references: Funct Neurol. 2009 Apr-Jun;24(2):89-92
references: 19775536
references: Science. 1999 Dec 17;286(5448):2352-5
references: 10600748
references: Nat Neurosci. 2002 Dec;5(12):1288-93
references: 12402041
references: Chem Res Toxicol. 2001 Mar;14(3):280-94
references: 11258977
references: J Biol Chem. 2006 Jun 16;281(24):16419-27
references: 16624814
references: J Neurosci. 2006 Sep 13;26(37):9439-47
references: 16971528
references: Proc Natl Sci Counc Repub China B. 2000 Jan;24(1):1-13
references: 10786933
references: Neuromolecular Med. 2002;1(1):1-31
references: 12025813
references: Environ Health Perspect. 2001 Feb;109(2):133-8
references: 11266322
references: Curr Alzheimer Res. 2005 Jan;2(1):65-77
references: 15977990
references: Nutr Rev. 2004 May;62(5):204-11
references: 15212320
references: Nat Med. 1995 Aug;1(8):829-32
references: 7585189
references: FEBS Lett. 2010 Oct 8;584(19):4259-67
references: 20849853
references: Neurosci Lett. 2010 Mar 8;471(3):134-8
references: 20096749
references: Mol Neurobiol. 2000 Aug-Dec;22(1-3):81-98
references: 11414282
references: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11049-53
references: 10500121
references: Circulation. 2004 May 25;109(20):2448-53
references: 15136500
references: Brain Res. 2007 Oct 3;1172:48-59
references: 17803971
references: Biochim Biophys Acta. 2000 Jul 26;1502(1):172-87
references: 10899442
references: J Gerontol A Biol Sci Med Sci. 2005 Jun;60(6):736-43
references: 15983176
references: Biochemistry. 2004 Oct 26;43(42):13532-40
references: 15491160
references: Neurosci Lett. 2000 Jan 14;278(3):169-72
references: 10653020
references: Biochem Soc Trans. 1999 Feb;27(2):234-42
references: 10093740
references: J Biol Chem. 2002 Aug 23;277(34):30574-80
references: 12058035