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

   
@article{APS11275,
	author = {Yue-yao Feng and Jing-ran Hao and Yu-jie Zhang and Tong-tong Qiu and Meng-lin Zhang and Wei Qiao and Jin-jin Wu and Ping Qiu and Chao-fan Xu and Yin-liang Zhang and Chun-yuan Du and Zhe Pan and Yong-sheng Chang},
	title = {Krüppel-like factor 9 alleviates Alzheimer’s disease via IDE-mediated Aβ degradation},
	journal = {Acta Pharmacologica Sinica},
	volume = {46},
	number = {6},
	year = {2025},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11275}
}