Green Tea (-)-epigallocatechin-3-gallate inhibits [beta]-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-[kappa]B pathways in mice

Alzheimer's disease (AD) is characterized by the extracellular deposition of [beta]-amyloid peptide (A[beta]) in cerebral plaques. A[beta] 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 A[beta] through the change of A[beta]-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 [micro]g A[[beta].sub.1-42]. EGCG dose-dependently reduced the A[[beta].sub.1-42]-induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. A[[beta].sub.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 A[beta] 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-[kappa]B in the A[[beta].sub.1-42]-injected mouse brains. In addition, EGCG inhibited A[[beta].sub.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 A[beta] levels. Moreover, EGCG inhibited the fibrillization of A[beta] 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.