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

Alzheimer disease (AD) is characterized by deposition of amyloid-β (Aβ). Decreased Aβ clearance in sporadic AD suggests that enhancing clearance is a potential therapeutic strategy. We previously identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ-degrading protease, with reduced mRNA expression in AD brains. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, upregulates KLK7 expression in astrocytes; however, the underlying regulatory mechanism is unclear. We investigated whether NMDA receptor signaling regulates KLK7 mRNA expression via nuclear factor-κB (NF-κB) in astrocytes, assessed the impact of NF-κB pathway inhibition on KLK7 expression and Aβ degradation, analyzed AD brain transcriptomic data for NF-κB family expression and its correlation with KLK7, and evaluated the in vivo effects of an NF-κB inhibitor on Klk7 expression and Aβ levels. NMDA receptor signaling negatively regulated KLK7 mRNA expression through NF-κB. In astrocytes, pharmacological inhibition of the NF-κB pathway increased KLK7 expression and promoted Aβ degradation. In AD brains, NF-κB family mRNA levels were elevated and negatively correlated with KLK7 mRNA expression. In vivo, injection of an NF-κB inhibitor significantly upregulated Klk7 and reduced Aβ levels. The astrocytic NMDA receptor–NF-κB signaling axis negatively regulates KLK7 expression and modulates KLK7-mediated Aβ clearance, supporting therapeutic strategies that target this pathway to enhance Aβ degradation.