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

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...

Full description

Saved in:
Bibliographic Details
Published in:Cell & bioscience Vol. 12; no. 1; pp. 1 - 18
Main Authors: Yao, Yuyuan, Ren, Zhichu, Yang, Ruihan, Mei, Yilan, Dai, Yuying, Cheng, Qian, Xu, Chong, Xu, Xiaogang, Wang, Sanying, Kim, Kyoung Mi, Noh, Ji Heon, Zhu, Jian, Zhao, Ningwei, Liu, Yong U., Mao, Genxiang, Sima, Jian
Format: Journal Article
Language:English
Published: London BioMed Central 04.11.2022
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Advertising executives
Aging
Alzheimer's disease
Analysis
Animal models
Axons
Biomedical and Life Sciences
Cell Biology
Cell culture
Cognitive ability
Drug development
Drug discovery
Dystrophy
Experiments
Genetic engineering
Homeostasis
Life Sciences
Ligases
Microbiology
Mitochondria
Mitochondrial protection
Morphology
Neurobiology
Neurodegenerative diseases
Neuroprotection
NRF2
Oxidative stress
Pathogenesis
Pathology
Peptides
Proteomics
SAL
SIRT3
Stem Cells
Surface plasmon resonance
Target marketing
Toxicity
Transgenic mice
Ubiquitin
Ubiquitin-protein ligase
Mitochondrial protection
Alzheimer’s disease
NRF2
SAL
SIRT3
ISSN:2045-3701, 2045-3701
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2045-3701
2045-3701
DOI:10.1186/s13578-022-00918-z