{"title":"Alisol A通过AMPK/NAMPT/ sirt1介导的胆固醇和自噬调节改善血管认知障碍。","authors":"Ping Xu, Wen Zhou, Shida Wang, Linjiao Wang, Yu Bai, Shan Xing, Wenda Xue, Meng Li, Jun Shi, Haoxin Wu","doi":"10.7150/thno.112661","DOIUrl":null,"url":null,"abstract":"<p><p>Atherosclerosis-related vascular cognitive impairment (VCI) is associated with dysregulated cholesterol metabolism and impaired autophagy. Alisol A, a natural tetracyclic triterpenoid derived from the traditional ZeXieYin Formula, has demonstrated anti-atherosclerotic and neuroprotective effects. However, its role in modulating brain cholesterol homeostasis and mitophagy in VCI remains largely unexplored. <b>Methods:</b> To elucidate the mechanism of Alisol A and evaluate its translational relevance, we employed an <i>Ldlr<sup>-/-</sup></i> mouse model of VCI induced by a high-fat diet and left common carotid artery ligation. Alisol A was administered intragastrically, and cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition tests. To probe the role of NAMPT, pharmacological inhibition and lentiviral overexpression strategies were applied. Mechanistic investigations included Western blotting, immunofluorescence, and transmission electron microscopy to examine cholesterol metabolism, oxidative stress, mitophagy, and synaptic plasticity. Additionally, molecular docking, surface plasmon resonance, and lipidomic profiling were used to explore Alisol A-NAMPT binding and downstream regulatory pathways. <b>Results:</b> Alisol A significantly ameliorated cognitive impairment in <i>Ldlr<sup>-/-</sup></i> mice. Mechanistically, it restored cholesterol homeostasis by activating the AMPK/NAMPT/SIRT1 signaling axis, upregulated UCP2 to suppress oxidative stress, and inhibited glial activation, thereby preserving neuronal structure and function. Additionally, Alisol A reactivated mitophagic flux by enhancing PINK1/PARKIN signaling and facilitating the clearance of damaged mitochondria, ultimately improving mitochondrial function. NAMPT was identified as a key molecular target mediating these neuroprotective effects. <b>Conclusion:</b> Alisol A confers neuroprotection in VCI by regulating cholesterol metabolism, attenuating oxidative stress, and restoring mitophagy via NAMPT-mediated signaling. These findings highlight its therapeutic potential in atherosclerosis-related cognitive decline.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9415-9446"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486161/pdf/","citationCount":"0","resultStr":"{\"title\":\"Alisol A ameliorates vascular cognitive impairment via AMPK/NAMPT/SIRT1-mediated regulation of cholesterol and autophagy.\",\"authors\":\"Ping Xu, Wen Zhou, Shida Wang, Linjiao Wang, Yu Bai, Shan Xing, Wenda Xue, Meng Li, Jun Shi, Haoxin Wu\",\"doi\":\"10.7150/thno.112661\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Atherosclerosis-related vascular cognitive impairment (VCI) is associated with dysregulated cholesterol metabolism and impaired autophagy. Alisol A, a natural tetracyclic triterpenoid derived from the traditional ZeXieYin Formula, has demonstrated anti-atherosclerotic and neuroprotective effects. However, its role in modulating brain cholesterol homeostasis and mitophagy in VCI remains largely unexplored. <b>Methods:</b> To elucidate the mechanism of Alisol A and evaluate its translational relevance, we employed an <i>Ldlr<sup>-/-</sup></i> mouse model of VCI induced by a high-fat diet and left common carotid artery ligation. Alisol A was administered intragastrically, and cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition tests. To probe the role of NAMPT, pharmacological inhibition and lentiviral overexpression strategies were applied. Mechanistic investigations included Western blotting, immunofluorescence, and transmission electron microscopy to examine cholesterol metabolism, oxidative stress, mitophagy, and synaptic plasticity. Additionally, molecular docking, surface plasmon resonance, and lipidomic profiling were used to explore Alisol A-NAMPT binding and downstream regulatory pathways. <b>Results:</b> Alisol A significantly ameliorated cognitive impairment in <i>Ldlr<sup>-/-</sup></i> mice. Mechanistically, it restored cholesterol homeostasis by activating the AMPK/NAMPT/SIRT1 signaling axis, upregulated UCP2 to suppress oxidative stress, and inhibited glial activation, thereby preserving neuronal structure and function. Additionally, Alisol A reactivated mitophagic flux by enhancing PINK1/PARKIN signaling and facilitating the clearance of damaged mitochondria, ultimately improving mitochondrial function. NAMPT was identified as a key molecular target mediating these neuroprotective effects. <b>Conclusion:</b> Alisol A confers neuroprotection in VCI by regulating cholesterol metabolism, attenuating oxidative stress, and restoring mitophagy via NAMPT-mediated signaling. These findings highlight its therapeutic potential in atherosclerosis-related cognitive decline.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 18\",\"pages\":\"9415-9446\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486161/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.112661\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.112661","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Alisol A ameliorates vascular cognitive impairment via AMPK/NAMPT/SIRT1-mediated regulation of cholesterol and autophagy.
Atherosclerosis-related vascular cognitive impairment (VCI) is associated with dysregulated cholesterol metabolism and impaired autophagy. Alisol A, a natural tetracyclic triterpenoid derived from the traditional ZeXieYin Formula, has demonstrated anti-atherosclerotic and neuroprotective effects. However, its role in modulating brain cholesterol homeostasis and mitophagy in VCI remains largely unexplored. Methods: To elucidate the mechanism of Alisol A and evaluate its translational relevance, we employed an Ldlr-/- mouse model of VCI induced by a high-fat diet and left common carotid artery ligation. Alisol A was administered intragastrically, and cognitive function was assessed using the Morris water maze, Y-maze, and novel object recognition tests. To probe the role of NAMPT, pharmacological inhibition and lentiviral overexpression strategies were applied. Mechanistic investigations included Western blotting, immunofluorescence, and transmission electron microscopy to examine cholesterol metabolism, oxidative stress, mitophagy, and synaptic plasticity. Additionally, molecular docking, surface plasmon resonance, and lipidomic profiling were used to explore Alisol A-NAMPT binding and downstream regulatory pathways. Results: Alisol A significantly ameliorated cognitive impairment in Ldlr-/- mice. Mechanistically, it restored cholesterol homeostasis by activating the AMPK/NAMPT/SIRT1 signaling axis, upregulated UCP2 to suppress oxidative stress, and inhibited glial activation, thereby preserving neuronal structure and function. Additionally, Alisol A reactivated mitophagic flux by enhancing PINK1/PARKIN signaling and facilitating the clearance of damaged mitochondria, ultimately improving mitochondrial function. NAMPT was identified as a key molecular target mediating these neuroprotective effects. Conclusion: Alisol A confers neuroprotection in VCI by regulating cholesterol metabolism, attenuating oxidative stress, and restoring mitophagy via NAMPT-mediated signaling. These findings highlight its therapeutic potential in atherosclerosis-related cognitive decline.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.