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Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer’s disease via modulating neuropathology and gut microbiota

Acta Pharmacologica Sinica volume 46, pages 1813–1833 (2025)Cite this article

Abstract

Amyloid-beta (Aβ) aggregation, phosphorylated tau accumulation and neuroinflammation are considered as three hallmarks of Alzheimer’s disease (AD). Rhynchophylline (RN), the major alkaloid of a Chinese medicinal plant Uncaria rhynchophylla, has been shown to possess potent anti-AD effects. This study explored the effects of RN on Aβ pathology, tauopathy, and neuroinflammation using three AD mouse models, including TgCRND8, 3×Tg-AD, and 5×FAD, with RN treatment lasting for 4, 6, and 6 months, respectively, followed by behavioral tests and biological assays. In addition, BV2 cells were employed to further evaluate the biological effects of RN. RN treatment improved cognitive functions by reducing anxiety-like behaviors, enhancing recognition ability, and ameliorating learning impairments. It modulated Aβ processing through reducing the Aβ-producing enzyme activities and enhancing degradation enzyme activities, thereby diminishing Aβ accumulation. RN also decreased hyperphosphorylated tau proteins at Thr181, Thr205, Ser396, and Ser404 sites. Moreover, RN diminished neuroinflammation by reducing microglia and astrocyte activation and lowering the release of inflammatory cytokines. Furthermore, RN treatment could restore gut microbiota dysbiosis in 5×FAD mice. In BV2 cells, knockdown of p53, HDAC2, and Galectin-3 markedly enhanced the anti-inflammatory effects of RN. Overall, the anti-AD properties of RN were attributed to its regulation of multiple biological pathways, including regulation of the p53/PINK1 signaling pathway, inhibition of the HDAC2/AMPK signaling pathway, suppression of the Galectin-3/C/EBPβ/AEP signaling pathway, and modulation of gut microflora dysbiosis. This pioneering study unambiguously revealed the effects of RN on cognitive impairments, APP processing, tauopathy, and neuroinflammation in different transgenic mouse models with differing AD burdens, highlighting its potential as an anti-AD therapeutic agent and enhancing the scientific basis for its clinical use in treating AD.

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Fig. 1: Schematic illustration of the experiment procedures on the investigation of the neuroprotective effects of RN.
Fig. 2: RN ameliorated cognitive impairments and behaviors of TgCRND8 mice.
Fig. 3: RN alleviated the Aβ and tau pathology, inhibited neuroinflammation, and modulated p53/PINK1 pathway in TgCRND8 mice.
Fig. 4: RN ameliorated the cognitive impairments and behaviors of 3×Tg-AD mice.
Fig. 5: RN suppressed the Aβ and tau pathology, decreased the neuroinflammation, and inhibited the activation of Galectin-3/C/EBPβ/AEP pathway in 3×Tg-AD mice.
Fig. 6: Effects of RN on the cognitive impairments and behaviors of 5×FAD mice.
Fig. 7: RN reduced the Aβ and tau pathology, alleviated the neuroinflammation and suppressed the activation of HDAC2/AMPKα1 pathway in 5×FAD mice.
Fig. 8: RN regulated the gut microbiota imbalance of 5×FAD mice.
Fig. 9: Silencing of p53, Galectin-3, and HDAC2 enhanced the inhibitory effects of RN against inflammatory response.
Fig. 10: Silencing of p53, Galectin-3, and HDAC2 enhanced the regulatory effects of RN against the activation of the p53/PINK1 pathway, Galectin-3/C/EBPβ/AEP pathway, and HDAC2/AMPKα1 pathway in the Αβ42-stimulated BV2 cells, respectively.
Fig. 11: The molecular mechanisms underlying the anti-AD effects of RN in the TgCRND8, 3×Tg-AD, and 5×FAD transgenic AD mouse models (Created with BioRender.com).

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Funding

This work was supported by the National Natural Science Foundation of China (Project No. 82104414), Guangdong Basic and Applied Basic Research Foundation (Project No. 2019A1515011257 and 2022A1515011682), and a Direct Grant from the Faculty of Medicine, The Chinese University of Hong Kong (Project No. 2021.071).

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Authors and Affiliations

  1. School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China

    Mei Zhong, Qing-qing Xu, Wen Yang, Zhi-xiu Lin & Yan-fang Xian

  2. Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, International Joint Research Center of Human-machine Intelligent Collaborative for Tumor Precision Diagnosis and Treatment of Hainan Province, Hainan Provincial Key Laboratory of Research and Development on Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou, 571199, China

    Mei Zhong

  3. College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

    Ming-qing Huang

  4. Key Laboratory of Chinese Medicinal Resource from Lingnan (Ministry of Education), School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Ruo-ting Zhan

  5. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Ruo-ting Zhan & Xiao-qi Huang

  6. Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, N.T., Hong Kong SAR, China

    Zhi-xiu Lin

  7. Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China

    Zhi-xiu Lin

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  1. Mei Zhong
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  2. Qing-qing Xu
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  3. Ming-qing Huang
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  4. Ruo-ting Zhan
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  5. Xiao-qi Huang
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  6. Wen Yang
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  7. Zhi-xiu Lin
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  8. Yan-fang Xian
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Contributions

YFX and ZXL conceived the research idea and designed the experimental protocols. MZ performed the experiments and collected the experimental data. RTZ, XQH, QQX, and WY helped with the data analysis. MZ drafted the manuscript. MQH, ZXL, and YFX revised the manuscript. All authors read and approved the final manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding authors

Correspondence to Zhi-xiu Lin or Yan-fang Xian.

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Ethics approval and consent to participate

All experimental procedures were approved by the Animal Experimentation Ethics Committee of CUHK (Ref. No.: 21/067/NSF).

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Zhong, M., Xu, Qq., Huang, Mq. et al. Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of Alzheimer’s disease via modulating neuropathology and gut microbiota. Acta Pharmacol Sin 46, 1813–1833 (2025). https://doi.org/10.1038/s41401-025-01475-0

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