Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway
Abstract Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective effi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-022-00918-z |
| _version_ | 1828095015359873024 |
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| author | Yuyuan Yao Zhichu Ren Ruihan Yang Yilan Mei Yuying Dai Qian Cheng Chong Xu Xiaogang Xu Sanying Wang Kyoung Mi Kim Ji Heon Noh Jian Zhu Ningwei Zhao Yong U. Liu Genxiang Mao Jian Sima |
| author_facet | Yuyuan Yao Zhichu Ren Ruihan Yang Yilan Mei Yuying Dai Qian Cheng Chong Xu Xiaogang Xu Sanying Wang Kyoung Mi Kim Ji Heon Noh Jian Zhu Ningwei Zhao Yong U. Liu Genxiang Mao Jian Sima |
| author_sort | Yuyuan Yao |
| collection | DOAJ |
| description | Abstract Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. Results SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Conclusions Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD. |
| first_indexed | 2024-04-11T07:06:01Z |
| format | Article |
| id | doaj.art-bd8512ee42134fcdb40b5ed7e528eb29 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-11T07:06:01Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-bd8512ee42134fcdb40b5ed7e528eb292022-12-22T04:38:23ZengBMCCell & Bioscience2045-37012022-11-0112111810.1186/s13578-022-00918-zSalidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathwayYuyuan Yao0Zhichu Ren1Ruihan Yang2Yilan Mei3Yuying Dai4Qian Cheng5Chong Xu6Xiaogang Xu7Sanying Wang8Kyoung Mi Kim9Ji Heon Noh10Jian Zhu11Ningwei Zhao12Yong U. Liu13Genxiang Mao14Jian Sima15Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityZhejiang Provincial Key Lab of Geriatrics and Geriatrics, Institute of Zhejiang Province, Department of Geriatrics, Zhejiang HospitalZhejiang Provincial Key Lab of Geriatrics and Geriatrics, Institute of Zhejiang Province, Department of Geriatrics, Zhejiang HospitalDepartment of Biological Sciences, Chungnam National UniversityDepartment of Biochemistry, Chungnam National UniversityDepartment of Psychology, Eastern Illinois UniversityChina Exposomics InstituteLaboratory for Neuroscience in Health and Disease, Guangzhou First People’s Hospital, South China University of TechnologyZhejiang Provincial Key Lab of Geriatrics and Geriatrics, Institute of Zhejiang Province, Department of Geriatrics, Zhejiang HospitalLaboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical UniversityAbstract Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. Results SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Conclusions Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.https://doi.org/10.1186/s13578-022-00918-zAlzheimer’s diseaseMitochondrial protectionSALSIRT3NRF2 |
| spellingShingle | Yuyuan Yao Zhichu Ren Ruihan Yang Yilan Mei Yuying Dai Qian Cheng Chong Xu Xiaogang Xu Sanying Wang Kyoung Mi Kim Ji Heon Noh Jian Zhu Ningwei Zhao Yong U. Liu Genxiang Mao Jian Sima Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway Cell & Bioscience Alzheimer’s disease Mitochondrial protection SAL SIRT3 NRF2 |
| title | Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway |
| title_full | Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway |
| title_fullStr | Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway |
| title_full_unstemmed | Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway |
| title_short | Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway |
| title_sort | salidroside reduces neuropathology in alzheimer s disease models by targeting nrf2 sirt3 pathway |
| topic | Alzheimer’s disease Mitochondrial protection SAL SIRT3 NRF2 |
| url | https://doi.org/10.1186/s13578-022-00918-z |
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