EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP.
Estrogen depletion following menopause has been correlated with an increased risk of developing Alzheimer's disease (AD). We previously explored the beneficial effect of (-)-epigallocatechin-3-gallate (EGCG) on AD mice and found increased non-amyloidogenic processing of amyloid precursor protein (APP) through the α-secretase a disintegrin and metallopeptidase domain 10 (ADAM10). Our results in this study suggest that EGCG-mediated enhancement of non-amyloidogenic processing of APP is mediated by the maturation of ADAM10 via an estrogen receptor-α (ERα)/phosphoinositide 3-kinase/Ak-transforming dependent mechanism, independent of furin-mediated ADAM10 activation. These data support prior assertions that central selective ER modulation could be a therapeutic target for AD and support the use of EGCG as a well-tolerated alternative to estrogen therapy in the prophylaxis and treatment of this disease.
Fernandez
Jamie Winderbaum
JW
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Tampa, FL 33613, USA. jfernan1@health.usf.edu
Rezai-Zadeh
Kavon
K
Obregon
Demian
D
Tan
Jun
J
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D045683:Furin / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D002392:Catechin; C045651:epigallocatechin gallate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D045683:Furin; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse