Cornuside alleviates cognitive impairments induced by Aβ 1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.

Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 101511643 Publication Model: Electronic Cited Medium: Internet ISSN: 1758-9193 (Electronic) NLM ISO Abbreviation: Alzheimers Res Ther Subsets: MEDLINE

Original Publication: [London] : BioMed Central Ltd.

Mitophagy*/drug effects ; NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein*/drug effects ; Amyloid beta-Peptides*/toxicity ; Cognitive Dysfunction*/chemically induced ; Cognitive Dysfunction*/drug therapy ; Cognitive Dysfunction*/metabolism ; Peptide Fragments*/toxicity ; Neuroprotective Agents*/pharmacology; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Inflammasomes/drug effects ; Inflammasomes/metabolism ; Disease Models, Animal ; Neurons/drug effects ; Neurons/metabolism

Competing Interests: Declarations. Ethics approval and consent to participate: All animal procedures were approved by the Animal Care and Use Committee of China-Japan Friendship Hospital. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and neuroinflammation play crucial roles in its progression. Our previous studies found that cornuside from Cornus officinalis Sieb.Et Zucc is an anti-AD candidate, however, its underlying mechanism remains unknown. In the present study, AD mice were established by intracerebroventricular injection of Aβ 1-42 and treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated behavioral deficits, protected synaptic plasticity and relieved neuronal damage in Aβ 1-42 induced mice. Importantly, cornuside decreased NLRP3 inflammasome activation, characterized by decreased levels of NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. Furthermore, cornuside promoted mitophagy accompanied by decreasing SQSTM1/p62 and promoting LC3B-I transforming into LC3B-II, via Pink1/Parkin signaling instead of FUNDC1 or BNIP3 pathways. In order to investigate the relationship between NLRP3 inflammasome and mitophagy in the neuroprotective mechanism of cornuside, we established an in-vitro model in BV2 cells exposed to LPS and Aβ 1-42 . And cornuside inhibited NLRP3 inflammasome activation and subsequent cytokine release, also protected neurons from damaging factors in microenvironment of conditional culture. Cornuside improved mitochondrial function by promoting oxidative phosphorylation and glycolysis, decreasing the production of ROS and mitochondrial membrane potential depolarization. Besides, mitophagy was also facilitated with increased colocalization of MitoTracker with LC3B and Parkin, and Pink1/Parkin, FUNDC1 and BNIP3 pathways were all involved in the mechanism of cornuside. By blocking the formation of autophagosomes by 3-MA, the protective effects on mitochondria, the inhibition on NLRP3 inflammasome as well as neuronal protection in conditional culture were eliminated. There is reason to believe that the promotion of mitophagy plays a key role in the NLRP3 inhibition of cornuside. In conclusion, cornuside re-establishes the mitophagy flux which eliminates damaged mitochondria and recovers mitochondrial function, both of them are in favor of inhibiting NLRP3 inflammasome activation, then alleviating neuronal and synaptic damage, and finally improving cognitive function.
(© 2025. The Author(s).)

Erratum in: Alzheimers Res Ther. 2025 Mar 19;17(1):63. doi: 10.1186/s13195-025-01715-9.. (PMID: 40108656)

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82404883 National Natural Science Foundation of China; 82273815 National Natural Science Foundation of China; 82273809 National Natural Science Foundation of China; ZRJY2023-QM10 National High Level Hospital Clinical Research Funding & Elite Medical Professionals Project of China-Japan Friendship Hospital; ZRJY2023-QM28 National High Level Hospital Clinical Research Funding & Elite Medical Professionals Project of China-Japan Friendship Hospital; ZRJY2024-BJ01 National High Level Hospital Clinical Research Funding & Elite Medical Professionals Project of China-Japan Friendship Hospital; 2024-NHLHCRF-JBGS-WZ-07 National High Level Hospital Clinical Research Funding & Elite Medical Professionals Project of China-Japan Friendship Hospital; 3332023096 Central Universities Fundamental for Basic Scientific Research of Peking Union Medical College

Keywords: Alzheimer’s disease; Cornuside; Mitophagy; NLRP3; Neuroprotection

0 (NLR Family, Pyrin Domain-Containing 3 Protein)
0 (Amyloid beta-Peptides)
0 (Peptide Fragments)
0 (Nlrp3 protein, mouse)
0 (amyloid beta-protein (1-42))
0 (Inflammasomes)
0 (Neuroprotective Agents)

Date Created: 20250219 Date Completed: 20250509 Latest Revision: 20250509

20250509

PMC11837312

10.1186/s13195-025-01695-w

39972387