A new andrographolide derivative ADA targeting SIRT3-FOXO3a signaling mitigates cognitive impairment by activating mitophagy and inhibiting neuroinflammation in Apoe4 mice

Yunfeng Zhou; Qian Zhao; Yixuan Zhang; Lulu Di; Feng Xue; Wangjun Xu; Weiping Gao; Yukun Guo; Yangyang He; Jiejian Kou; Ying Qin; Xinmei Xie; Lida Du; Guang Han; Xiaobin Pang

doi:10.1016/j.phymed.2023.155298

A new andrographolide derivative ADA targeting SIRT3-FOXO3a signaling mitigates cognitive impairment by activating mitophagy and inhibiting neuroinflammation in Apoe4 mice

Phytomedicine. 2024 Feb:124:155298. doi: 10.1016/j.phymed.2023.155298. Epub 2023 Dec 17.

Authors

Yunfeng Zhou¹, Qian Zhao², Yixuan Zhang³, Lulu Di², Feng Xue², Wangjun Xu², Weiping Gao², Yukun Guo², Yangyang He⁴, Jiejian Kou³, Ying Qin², Xinmei Xie⁵, Lida Du⁶, Guang Han⁷, Xiaobin Pang⁸

Affiliations

¹ Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China; State Key Laboratroy of Antiviral Drugs, Henan University, Kaifeng 475004, China.
² Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China.
³ Huaihe Hosptial of Henan University, Kaifeng 475000, China.
⁴ Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China; Institutes of Traditional Chinese Medicine, Henan University, Kaifeng 475004, China; State Key Laboratroy of Antiviral Drugs, Henan University, Kaifeng 475004, China.
⁵ Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China; State Key Laboratroy of Antiviral Drugs, Henan University, Kaifeng 475004, China. Electronic address: xxm@vip.henu.edu.cn.
⁶ Institute of Molecular Medicine & Innovative Pharmaceutics, Qingdao University, Qingdao 266071, China. Electronic address: l.du@utoronto.ca.
⁷ Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China; State Key Laboratroy of Antiviral Drugs, Henan University, Kaifeng 475004, China. Electronic address: hang@vip.henu.edu.cn.
⁸ Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, School of Pharmacy, Henan University, Kaifeng 475004, China; Institutes of Traditional Chinese Medicine, Henan University, Kaifeng 475004, China; State Key Laboratroy of Antiviral Drugs, Henan University, Kaifeng 475004, China. Electronic address: pxb@vip.henu.edu.cn.

PMID: 38185066
DOI: 10.1016/j.phymed.2023.155298

Abstract

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and mitophagy deficit was identified as the typical abnormality in early stage of AD. The neuroprotective effect of andrographolide (AGA) has been confirmed, anda acetylated derivative of AGA (3,14,19-triacetylandrographolide, ADA) was considered to have stronger efficacy.

Purpose: The current study aims to investigate the impact of ADA on cognitive ability in a sporadic AD model and explore its potential mechanism.

Study design/ methods: Apoe4 mouse was adopted for evaluating the impact of AGA on cognitive impairment through a serious of behavioral tests. The molecular mechanism of ADA involved in mitophagy and neuroinflammation was investigated in detailby Western blot, ELISA, immunofluorescence and transmission electron microscopy in Apoe4 mice, as well as Apoe4-transfected BV2 cells and HT22 cells.

Results: ADA application significantly improved cognitive impairment of Apoe4 mice, and lessened Aβ load and neuronal damage, which has stronger activity than its prototype AGA. Accumulated mitophagy markers LC3II, P62, TOM20, PINK1 and Parkin, and decreased mitophagy receptor BNIP3 in hippocampus of Apoe4 mice were greatly reversed after ADA treatment. Meanwhile, ADA promoted the recruitment of BNIP3 to mitochondria, and the transport of damaged mitochondria to lysosome, indicating that disturbed mitophagy in AD mice was restored by ADA. Inhibited SIRT3 and FOXO3a in Apoe4 mice brains were elevated after ADA treatment. ADA also lightened the neuroinflammation caused by NLRP3 inflammasome activation. Additionally, damaged mitophagy and/or activated NLRP3 inflammasome were also observed in BV2 cells and HT22 cells transfected with Apoe4, all of which were rescued by ADA incubation. Noteworthily, SIRT3 inhibitor 3-TYP could abolish the impact of ADA on mitophagy and NLRP3 inflammasome in vitro.

Conclusion: ADA exerted stronger cognition-enhancing ability in relative to AGA, and ADA could repaire mitophagy deficiency via SIRT3-FOXO3a pathway, and subsequently inhibite NLRP3 inflammasome to mitigate AD pathology.

Keywords: 3,14,19-triacetylandrographolide; Alzheimer's disease; Mitophagy; NLRP3 inflammasome; SIRT3-FOXO3a pathway.

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Animals
Apolipoprotein E4 / pharmacology
Cognitive Dysfunction* / drug therapy
Cognitive Dysfunction* / metabolism
Diterpenes*
Inflammasomes / metabolism
Mice
Mitophagy
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Neuroinflammatory Diseases
Sirtuin 3*

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Inflammasomes
Sirtuin 3
Apolipoprotein E4
andrographolide
Diterpenes