Abstract
Pyroptosis-mediated neuron death plays a crucial role in neurodegenerative diseases, such as Alzheimer’s disease (AD). However, the effect of 1,7-diphenyl-4-hepten-3-one (C1), a natural diarylheptanoid, on AD is unclear. Herein, we investigated the therapeutic effect of C1 on APP/PS1 mice and β-amyloid (Aβ)-induced HT22 cells. Our findings showed that C1 attenuated cognitive impairment and mitigated pathological damage in APP/PS1 mice. Furthermore, we found that C1 prevented oxidative stress damage and decreased the levels of pyroptosis-related proteins. In vitro experiments showed that C1 can improve the proliferation of Aβ-induced HT22 cells and decrease the levels of pyroptosis-related proteins in them. When Nrf2 was silenced, the positive effects of C1 in inhibiting pyroptosis were inhibited. Particularly, the production of pyroptosis-associated proteins, including NLRP3, GSDMD, and caspase-1, and the secretion of pro-inflammatory molecules, including IL-1 and IL-18, were increased. Altogether, these findings indicate that C1 can mitigate AD-like pathology via the inhibition of pyroptosis by activating the Nrf2 pathway. We believe that this study can provide alternative strategies for the prevention and treatment of AD.
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Data and materials are available in the paper.
Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
β-Amyloid
- NLRP3:
-
NOD-like receptor thermal protein domain associated protein 3
- IL-18:
-
Interleukin-18
- IL-1β:
-
Interleukin-1β
- GSDMD:
-
Gasdermin-D
- Nrf2:
-
Nuclear factor erythroid 2-related factor 2
- ROS:
-
Reactive oxygen species
- PFA:
-
Paraformaldehyde
- BSA:
-
Bovine serum albumin
- TNF-α:
-
Tumor necrosis factor-α
- CCK-8:
-
Cell counting kit-8
- LDH:
-
Lactate dehydrogenase
- SOD:
-
Superoxide dismutase
- MDA:
-
Malonaldehyde
- GSH:
-
L-Glutathione
- AOM:
-
Alpinia oxyphylla Mique
- CCK-F:
-
Cell fluorescence counting kit-F
- Edu:
-
5-Ethynyl-2′-deoxyuridine
- Mod:
-
Molde group
- C1L:
-
C1 low-dose group
- C1H:
-
C1 high-dose group
- MFI:
-
Median fluorescence intensity
- AOD:
-
Average optical density
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Funding
The authors appreciate the support from the Natural Science Foundation of Liaoning Province of China (grant no. 20170540201) and the Key Research and Development Plan of Anhui Province in 2022 (grant no. 2022e07020065).
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Yu-Sheng Shi: conceptualization, methodology, software, and writing—original draft. Yan Zhang: writing—original draft, data curation, and investigation. Xiao Luo: validation and resources. Hong-Kai Yang: validation and resources. Yong-Sheng He: methodology, writing—review and editing, and funding acquisition. The authors declare that all data were generated in-house and that no paper mill was used.
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The animals were acclimated for 1 week before experimentation. This study was conducted following the guidelines of the Ethics Committee of Dalian Minzu University (Dalian, China) (Approval AEWC-20210303-1).
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Shi, YS., Zhang, Y., Luo, X. et al. 1,7-diphenyl-4-hepten-3-one mitigates Alzheimer’s-like pathology by inhibiting pyroptosis via activating the Nrf2 pathway. Naunyn-Schmiedeberg's Arch Pharmacol 397, 3065–3075 (2024). https://doi.org/10.1007/s00210-023-02765-2
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DOI: https://doi.org/10.1007/s00210-023-02765-2