2. Academic Validation
  3. Salidroside reduces neuropathology in Alzheimer's disease models by targeting NRF2/SIRT3 pathway

Salidroside reduces neuropathology in Alzheimer's disease models by targeting NRF2/SIRT3 pathway

  • Cell Biosci. 2022 Nov 4;12(1):180. doi: 10.1186/s13578-022-00918-z.
Yuyuan Yao # 1,  Zhichu Ren # 1,  Ruihan Yang 1,  Yilan Mei 1,  Yuying Dai 1,  Qian Cheng 1,  Chong Xu 1,  Xiaogang Xu 2,  Sanying Wang 2,  Kyoung Mi Kim 3,  Ji Heon Noh 4,  Jian Zhu 5,  Ningwei Zhao 6,  Yong U Liu 7,  Genxiang Mao 8,  Jian Sima 9
Affiliations

Affiliations

  • 1 Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Zhejiang Provincial Key Lab of Geriatrics and Geriatrics, Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310030, China.
  • 3 Department of Biological Sciences, Chungnam National University, Daejeon, 34134, Korea.
  • 4 Department of Biochemistry, Chungnam National University, Daejeon, 34134, Korea.
  • 5 Department of Psychology, Eastern Illinois University, Charleston, IL, 61920, USA.
  • 6 China Exposomics Institute, 781 Cai Lun Road, Shanghai, 200120, China.
  • 7 Laboratory for Neuroscience in Health and Disease, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
  • 8 Zhejiang Provincial Key Lab of Geriatrics and Geriatrics, Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, Hangzhou, 310030, China. [email protected].
  • 9 Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. [email protected].
  • # Contributed equally.
PMID: 36333711 DOI: 10.1186/s13578-022-00918-z
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.

Keywords

Alzheimer’s disease; Mitochondrial protection; NRF2; SAL; SIRT3.

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