Krüppel样因子9通过IDE介导的Aβ降解缓解阿尔茨海默病，这一成果由天津医科大学常永生研究组经过不懈努力而取得。该研究于2025年2月17日发表于国际一流学术期刊《中国药理学报》杂志上。

研究人员表示，β-淀粉样蛋白（Aβ）在大脑中的沉积是阿尔茨海默病（AD）发病的关键因素。胰岛素降解酶（IDE）在Aβ生成和降解之间的平衡中起着关键作用。然而，IDE的调控机制还没有被完全理解。因此，揭示额外的IDE调控机制将有助于阐明AD的发病机制，并确定该疾病的关键治疗靶点。本研究发现全球Krüppel样因子9突变体（Klf9/）小鼠表现出认知功能受损。

此外，研究团队发现APPswe/PS1dE9 （APP/PS1）小鼠海马组织中Klf9的表达降低。本研究还表明，Klf9通过直接结合IDE并激活其转录，刺激IDE表达，促进Aβ降解过程。沉默IDE阻断了klf9诱导的Aβ降解过程。该研究组立体定向注射一种腺相关病毒（adeno-associated virthem），在Klf9 /研究发现，IDE在海马神经元中的过表达可改善认知缺陷，并降低Klf9/老鼠。

此外，该团队还将AAV-Klf9立体定向注射到APP/PS1小鼠海马神经元中，发现在APP/PS1小鼠海马神经元中过表达Klf9可改善认知缺陷并降低Aβ水平。这些发现表明，Klf9的下调可能是AD进展的关键因素，因为它通过降低IDE表达来降低Aβ清除率。Klf9的过表达或激活可能是预防AD发病机制的潜在策略。

附：英文原文

Title: Krüppel-like factor 9 alleviates Alzheimer’s disease via IDE-mediated Aβ degradation

Author: Feng, Yue-yao, Hao, Jing-ran, Zhang, Yu-jie, Qiu, Tong-tong, Zhang, Meng-lin, Qiao, Wei, Wu, Jin-jin, Qiu, Ping, Xu, Chao-fan, Zhang, Yin-liang, Du, Chun-yuan, Pan, Zhe, Chang, Yong-sheng

Issue&Volume: 2025-02-17

Abstract: The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer’s disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9/) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9/ mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9/ mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.

DOI: 10.1038/s41401-025-01491-0

Source: https://www.nature.com/articles/s41401-025-01491-0