EPIGALLOCATECHIN GALLATE INDUCES EXTRACELLULAR DEGRADATION OF AMYLOID β-PROTEIN BY INCREASING NEPRILYSIN SECRETION FROM ASTROCYTES THROUGH ACTIVATION OF ERK AND PI3K PATHWAYS

Amyloid-beta (AD) production and clearance in the brain is a crucial focus of investigations into the pathogenesis of Alzheimer disease. Imbalance between production and clearance leads to accumulation of AD. The important All-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), and defective enzyme expression may facilitate Ap deposition in sporadic late onset AD patients. It has been suggested that epigallocatechin gallate (EGCG), a member of the catechin family, might be an effective treatment for AD, because it has been shown to elevate NEP expression. Therefore, we examined whether catechins, which are functional components of common foods, could regulate the degradation of A beta by inducing NEP and IDE expression. We also investigated the role of catechins in activating intracellular signal transduction in astrocytes. Treatment of cultured rat astrocytes with EGCG significantly reduced the expression of NEP, but not IDE, in a concentration-and time-dependent manner. NEP expression in cultured astrocytes was suppressed by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), and reduced NEP expression was accompanied by an increase of NEP release into the extra cellular space (culture medium). Moreover, culture medium from EGCG-treated astrocytes facilitated the degradation of exogenous AD. These results suggest that EGCG may have a beneficial effect on AD by activating ERK-and PI3K-mediated pathways in astrocytes, thus increasing astrocyte secretion of NEP and facilitating degradation of A beta (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.