title: Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice.
abstract: Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques. Abeta is derived from the beta-amyloid precursor protein (APP) by the enzymes alpha-, beta- and gamma-secretase. Compounds that enhance alpha-secretase, but inhibit beta- or gamma-secretase activity, have therapeutic potential in the treatment of AD. Green tea, or its major polyphenolic compound, has been shown to have neuroprotective effects. In this study, we investigated the possible effects of (-)-epigallocatechin-3-gallate (EGCG) on memory dysfunction caused by Abeta through the change of Abeta-induced secretase activities. Mice were pretreated with EGCG (1.5 or 3 mg/kg body weight in drinking water) for 3 wk before intracerebroventricular administration of 0.5 microg Abeta(1-42). EGCG dose-dependently reduced the Abeta(1-42)-induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. Abeta(1-42) induced a decrease in brain alpha-secretase and increases in both brain beta- and gamma-secretase activities, which were reduced by EGCG. In the cortex and the hippocampus, expression of the metabolic products of the beta- and gamma-secretases from APP, C99, and Abeta also were dose-dependently suppressed by EGCG. Paralleled with the suppression of beta- and gamma-secretases by EGCG, we found that EGCG inhibited the activation of extracellular signal-regulated kinase and nuclear transcription factor-kappaB in the Abeta(1-42)-injected mouse brains. In addition, EGCG inhibited Abeta(1-42)-induced apoptotic neuronal cell death in the brain. To further test the ability of EGCG to affect memory, EGCG (3 mg/kg body weight) was administered in drinking water for 1 wk to genetically developed preseniline 2 (PS2) mutant AD mice. Compared with untreated mutant PS2 AD mice, treatment with EGCG enhanced memory function and brain alpha-secretase activity but reduced brain beta- and gamma-secretase activities as well as Abeta levels. Moreover, EGCG inhibited the fibrillization of Abeta in vitro with a half maximal inhibitory concentration of 7.5 mg/L. These studies suggest that EGCG may be a beneficial agent in the prevention of development or progression of AD.
authors: College of Pharmacy, Chungbuk National University 12, Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.
authors: Jae Woong
authors: JW
authors: Lee
authors: Yong Kyoung
authors: YK
authors: Lee
authors: Jung Ok
authors: JO
authors: Ban
authors: Tae Youl
authors: TY
authors: Ha
authors: Yeo Pyo
authors: YP
authors: Yun
authors: Sang Bae
authors: SB
authors: Han
authors: Ki Wan
authors: KW
authors: Oh
authors: Jin Tae
authors: JT
authors: Hong
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D028241:Camellia sinensis / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D002392:Catechin; C045651:epigallocatechin gallate; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases