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

Alzheimer disease (AD) is characterized by the deposition of amyloid-β peptide (Aβ). Decreased Aβ clearance is observed in sporadic AD patients, suggesting that enhancing Aβ clearance is a potential therapeutic approach for AD. We identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ-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-κB (NF-κB). Inhibition of NF-κB signaling pathway in astrocytes increases KLK7 expression and promotes Aβ degradation. Moreover, the mRNA expression level of the NF-κB family is elevated in AD brains and shows a negative correlation with KLK7 mRNA expression. Finally, the injection of an NF-κB inhibitor significantly upregulates Klk7 expression and reduces Aβ levels in vivo . These findings suggest that the NMDA receptor-NF-κB signaling axis in astrocytes negatively regulates KLK7 expression and modulates KLK7-mediated Aβ clearance.