GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection
Geniposidic 4-isoamyl ester (GENI) with anti-aging effects is a new iridoid glycoside derivative from <i>Gardenia jasminoides</i> Ellis found in our previous study. In this study, to indicate whether this compound has anti-Alzheimer’s disease (AD) effect, the galactose-induced AD mice an...
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2025-01-01
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| author | Ying Wang Lanjie Li Danni Chen Jiaheng Shan Meijuan Yi Hiroyuki Osada Minoru Yoshida Lan Xiang Jianhua Qi |
| author_facet | Ying Wang Lanjie Li Danni Chen Jiaheng Shan Meijuan Yi Hiroyuki Osada Minoru Yoshida Lan Xiang Jianhua Qi |
| author_sort | Ying Wang |
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| description | Geniposidic 4-isoamyl ester (GENI) with anti-aging effects is a new iridoid glycoside derivative from <i>Gardenia jasminoides</i> Ellis found in our previous study. In this study, to indicate whether this compound has anti-Alzheimer’s disease (AD) effect, the galactose-induced AD mice and naturally aging mice with AD were used to do drug efficacy evaluation. Furthermore, the Western blot, small interfering RNA (siRNA), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CESTA), liquid chromatography-tandem mass spectrometry (LC/MS-MS), adenosine 5′-monophosphate-activated protein kinase (AMPK) mutants and surface plasmon resonance (SPR) analysis were utilized to clarify the mechanism of action and identify target protein of this molecule. GENI exerts anti-AD efficacy in galactose-induced AD mice and naturally aging mice with AD through neuroprotection and modification of autophagy and neuron inflammation. Moreover, AMPK as the target protein of GENI to produce an anti-AD effect is identified and the ASP148, ASP157, and ASP166 of the AMPK α subunit and lysine (LYS)148, aspartic acid (ASP)156, LYS309, and ASP316 in the AMPK γ subunit as binding sites are confirmed. Meanwhile, the AMPK/unc-51-like autophagy-activating kinase 1 (ULK1)/microtubule-associated protein 1 light chain 3 beta (LC3B) and AMPK/mammalian target of rapamycin (mTOR) signaling pathways involved in anti-AD effects of GENI. The findings provide a new perspective on treating neurodegenerative diseases by activating AMPK for the energy metabolism disorder. |
| format | Article |
| id | doaj-art-5f8fcea7da3c4fd498998ad840749f09 |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-5f8fcea7da3c4fd498998ad840749f092025-01-24T13:19:20ZengMDPI AGAntioxidants2076-39212025-01-011415710.3390/antiox14010057GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and NeuroprotectionYing Wang0Lanjie Li1Danni Chen2Jiaheng Shan3Meijuan Yi4Hiroyuki Osada5Minoru Yoshida6Lan Xiang7Jianhua Qi8College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaChemical Biology Research Group, RIKEN Center for Sustainable Resource Science, wako, Saitama 351-0198, JapanChemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, JapanCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, ChinaGeniposidic 4-isoamyl ester (GENI) with anti-aging effects is a new iridoid glycoside derivative from <i>Gardenia jasminoides</i> Ellis found in our previous study. In this study, to indicate whether this compound has anti-Alzheimer’s disease (AD) effect, the galactose-induced AD mice and naturally aging mice with AD were used to do drug efficacy evaluation. Furthermore, the Western blot, small interfering RNA (siRNA), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CESTA), liquid chromatography-tandem mass spectrometry (LC/MS-MS), adenosine 5′-monophosphate-activated protein kinase (AMPK) mutants and surface plasmon resonance (SPR) analysis were utilized to clarify the mechanism of action and identify target protein of this molecule. GENI exerts anti-AD efficacy in galactose-induced AD mice and naturally aging mice with AD through neuroprotection and modification of autophagy and neuron inflammation. Moreover, AMPK as the target protein of GENI to produce an anti-AD effect is identified and the ASP148, ASP157, and ASP166 of the AMPK α subunit and lysine (LYS)148, aspartic acid (ASP)156, LYS309, and ASP316 in the AMPK γ subunit as binding sites are confirmed. Meanwhile, the AMPK/unc-51-like autophagy-activating kinase 1 (ULK1)/microtubule-associated protein 1 light chain 3 beta (LC3B) and AMPK/mammalian target of rapamycin (mTOR) signaling pathways involved in anti-AD effects of GENI. The findings provide a new perspective on treating neurodegenerative diseases by activating AMPK for the energy metabolism disorder.https://www.mdpi.com/2076-3921/14/1/57iridoid glycosideAMP-activated protein kinaseautophagyneuroprotectionAlzheimer’s diseasetarget identification |
| spellingShingle | Ying Wang Lanjie Li Danni Chen Jiaheng Shan Meijuan Yi Hiroyuki Osada Minoru Yoshida Lan Xiang Jianhua Qi GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection Antioxidants iridoid glycoside AMP-activated protein kinase autophagy neuroprotection Alzheimer’s disease target identification |
| title | GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection |
| title_full | GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection |
| title_fullStr | GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection |
| title_full_unstemmed | GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection |
| title_short | GENI as an AMPK Activator Binds α and γ Subunits and Improves the Memory Dysfunction of Alzheimer’s Disease Mouse Models via Autophagy and Neuroprotection |
| title_sort | geni as an ampk activator binds α and γ subunits and improves the memory dysfunction of alzheimer s disease mouse models via autophagy and neuroprotection |
| topic | iridoid glycoside AMP-activated protein kinase autophagy neuroprotection Alzheimer’s disease target identification |
| url | https://www.mdpi.com/2076-3921/14/1/57 |
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