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Background <p>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 <i>KLK7</i> expression in astrocytes; however, the underlying regulatory mechanism is unclear.</p> Methods <p>We investigated whether NMDA receptor signaling regulates <i>KLK7</i> mRNA expression via nuclear factor-κB (NF-κB) in astrocytes, assessed the impact of NF-κB pathway inhibition on <i>KLK7</i> expression and Aβ degradation, analyzed AD brain transcriptomic data for NF-κB family expression and its correlation with <i>KLK7</i>, and evaluated the <i>in vivo</i> effects of an NF-κB inhibitor on <i>Klk7</i> expression and Aβ levels.</p> Results <p>NMDA receptor signaling negatively regulated <i>KLK7</i> mRNA expression through NF-κB. In astrocytes, pharmacological inhibition of the NF-κB pathway increased <i>KLK7</i> expression and promoted Aβ degradation. In AD brains, NF-κB family mRNA levels were elevated and negatively correlated with <i>KLK7</i> mRNA expression. <i>In vivo</i>, injection of an NF-κB inhibitor significantly upregulated <i>Klk7</i> and reduced Aβ levels.</p> Conclusions <p>The astrocytic NMDA receptor–NF-κB signaling axis negatively regulates <i>KLK7</i> expression and modulates KLK7-mediated Aβ clearance, supporting therapeutic strategies that target this pathway to enhance Aβ degradation.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Yuki Sudo,
  • Chia-Jen Sung,
  • Rie Nakayoshi,
  • Honoka Kobayashi,
  • Kazunori Kikuchi,
  • Yung-Wen Chiu,
  • Sho Takatori,
  • Yukiko Hori,
  • Taisuke Tomita

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.