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<p>Alzheimer’s disease (AD) represents the most common manifestation of dementia. Cerebrovascular dysfunction constitutes one of the initial events in the pathogenic process of AD. Recently, our research group has reported that artemether, a first-line antimalarial drug approved by the FDA, exhibits a neuroprotective property. Nevertheless, the impact of artemether on cerebrovascular dysfunction, along with its underlying mechanisms, still awaits comprehensive elucidation. This study systematically investigated the neuroprotective effects of artemether against Aβ<sub>1-42</sub>-induced injury in brain microvascular endothelial cells and explored the underlying molecular mechanisms. Our findings demonstrate that artemether potently mitigates Aβ<sub>1-42</sub>-mediated cytotoxicity and endothelial barrier dysfunction in mouse brain microvascular endothelial cells. Moreover, artemether attenuated blood–brain barrier disruption by upregulating tight junction proteins OCLN, CLDN-5, and ZO-1. Further studies revealed that artemether treatment improved elevated ROS levels, the dissipation of mitochondrial membrane potential, and the decrease of ATP content. Immunoblotting analysis demonstrated that artemether stimulated the CAMKK2-AMPK kinase and its downstream target PGC1α. In addition, the blockage of the CAMKK2/AMPK/PGC1α pathway by inhibitor STO-609, Compound C, or knocking down the expression level of PGC1α with sgRNA significantly attenuated the neuroprotective activity of artemether. These results indicate the essential role of the CAMKK2/AMPK/PGC1α pathway in the protective effect of artemether in mouse brain microvascular endothelial cells. Similar results were obtained in Aβ<sub>1-42</sub>-treated human brain microvascular endothelial cells. In the AD mice model, we found that artemether treatment increased the expression level of ZO-1, CLDN-5, and OCLN of the AD mice model. Collectively, these findings demonstrate that artemether exerts neuroprotection against Aβ<sub>1-42</sub>-induced injury in brain microvascular endothelial cells through activation of the CAMKK2/AMPK/PGC1α signaling axis, which supports the protective effect of artemether in the prevention and treatment of AD through improving cerebrovascular dysfunction.</p> Graphical Abstract <p>Artemether protects blood–brain barrier damage through ameliorating Aβ<sub>1-42</sub>-induced mitochondrial dysfunction via the activation of CAMKK2/AMPK/PGC1α signaling pathway.</p> <p></p>

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Artemether Improves Aβ1-42-Induced Mitochondrial Dysfunction and Protects Against Blood–Brain Barrier Damage Through Activating the CAMKK2/AMPK/PGC1α Signaling Pathway

  • 期刊论文

  • 发表日期：

    2025年6月10日

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  • Jun Cai,
  • Yuxuan Liu,
  • Li Gong,
  • Shengfeng Deng,
  • Wenhua Zheng,
  • Shuai Li

摘要

Alzheimer’s disease (AD) represents the most common manifestation of dementia. Cerebrovascular dysfunction constitutes one of the initial events in the pathogenic process of AD. Recently, our research group has reported that artemether, a first-line antimalarial drug approved by the FDA, exhibits a neuroprotective property. Nevertheless, the impact of artemether on cerebrovascular dysfunction, along with its underlying mechanisms, still awaits comprehensive elucidation. This study systematically investigated the neuroprotective effects of artemether against Aβ1-42-induced injury in brain microvascular endothelial cells and explored the underlying molecular mechanisms. Our findings demonstrate that artemether potently mitigates Aβ1-42-mediated cytotoxicity and endothelial barrier dysfunction in mouse brain microvascular endothelial cells. Moreover, artemether attenuated blood–brain barrier disruption by upregulating tight junction proteins OCLN, CLDN-5, and ZO-1. Further studies revealed that artemether treatment improved elevated ROS levels, the dissipation of mitochondrial membrane potential, and the decrease of ATP content. Immunoblotting analysis demonstrated that artemether stimulated the CAMKK2-AMPK kinase and its downstream target PGC1α. In addition, the blockage of the CAMKK2/AMPK/PGC1α pathway by inhibitor STO-609, Compound C, or knocking down the expression level of PGC1α with sgRNA significantly attenuated the neuroprotective activity of artemether. These results indicate the essential role of the CAMKK2/AMPK/PGC1α pathway in the protective effect of artemether in mouse brain microvascular endothelial cells. Similar results were obtained in Aβ1-42-treated human brain microvascular endothelial cells. In the AD mice model, we found that artemether treatment increased the expression level of ZO-1, CLDN-5, and OCLN of the AD mice model. Collectively, these findings demonstrate that artemether exerts neuroprotection against Aβ1-42-induced injury in brain microvascular endothelial cells through activation of the CAMKK2/AMPK/PGC1α signaling axis, which supports the protective effect of artemether in the prevention and treatment of AD through improving cerebrovascular dysfunction.

Graphical Abstract

Artemether protects blood–brain barrier damage through ameliorating Aβ1-42-induced mitochondrial dysfunction via the activation of CAMKK2/AMPK/PGC1α signaling pathway.