Inhibition of NF-κB signaling pathway in astrocytes facilitates amyloid-β clearance by kallikrein-related peptidase 7

Abstract

Alzheimer disease (AD) is characterized by the deposition of amyloid-{beta} peptide (A{beta}). Decreased A{beta} clearance is observed in sporadic AD patients, suggesting that enhancing A{beta} clearance is a potential therapeutic approach for AD. We identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived A{beta}-degrading protease, and its mRNA expression is reduced in AD brains. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, upregulates KLK7 expression in astrocytes; however, the regulatory mechanism remains unclear. Here, we show that the NMDA receptor signaling negatively regulates KLK7 mRNA expression via nuclear factor-{kappa}B (NF-{kappa}B). Inhibition of NF-{kappa}B signaling pathway in astrocytes increases KLK7 expression and promotes A{beta} degradation. Moreover, the mRNA expression level of the NF-{kappa}B family is elevated in AD brains and shows a negative correlation with KLK7 mRNA expression. Finally, the injection of an NF-{kappa}B inhibitor significantly upregulates Klk7 expression and reduces A{beta} levels in vivo. These findings suggest that the NMDA receptor-NF-{kappa}B signaling axis in astrocytes negatively regulates KLK7 expression and modulates KLK7-mediated A{beta} clearance.