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Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer’s disease models

Acta Pharmacologica Sinica volume 45, pages 900–913 (2024)Cite this article

Abstract

Autophagy impairment is a key factor in Alzheimer’s disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson’s disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in AD models.

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Fig. 1: Cory improves cognitive functions and rescues memory deficiency in 5xFAD mice.
Fig. 2: Cory enhances autophagy and reduces APP/CTFs accumulation in 5xFAD mice.
Fig. 3: Cory enhances autophagy flux and lysosomal biogenesis in neuronal cell.
Fig. 4: Cory-induced autophagy was through the nuclear translocation of TFEB/TFE3.
Fig. 5: The translocation of Cory-mediated TFEB/TFE3 into the nucleus is dependent on the AKT/mTOR pathway.
Fig. 6: TRPML1 inhibition hinders Cory-induced TFEB/TFE3 nuclear translocation and autophagy activation.
Fig. 7: Cory reduces APP and CTFs protein levels in N2aSwedAPP cells.
Fig. 8: Cory activates TFEB/TFE3 in the hippocampus of 5xFAD mice.
Fig. 9: Schematic illustration of the mechanism in Cory-mediated autophagy.

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Acknowledgements

We would like to thank Mr. Alan Ho for provision of equipment and technical training. We would like to thank Dr. Martha Dahlen for her English editing of this manuscript. This study was supported by Hong Kong Health and Medical Research Fund (HMRF/17182551, HMRF/09203776) and the Hong Kong General Research Fund (CRF/C2011-21GF, HKBU 12101022) from Hong Kong Government. The study was partly supported by the Research Fund from Hong Kong Baptist University (HKBU/RC-IRCs/17-18/03, IRCMS/19-20/H02), GDSSIL/84-506/2019 and the National Natural Science Foundation of China (82074042).

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Authors and Affiliations

  1. Mr. & Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research (CPDR), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China

    Xin-jie Guan, Zhi-qiang Deng, Jia Liu, Cheng-fu Su, Benjamin Chun-Kit Tong, Zhou Zhu, Sravan Gopalkrishnashetty Sreenivasmurthy, Yu-xuan Kan, Ke-jia Lu, Carol Pui-Kei Chu, King-ho Cheung, Ashok Iyaswamy & Min Li

  2. Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China

    Xin-jie Guan, Zhi-qiang Deng, Jia Liu, Cheng-fu Su, Zhou Zhu, Yu-xuan Kan, King-ho Cheung, Ashok Iyaswamy & Min Li

  3. Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA

    Sravan Gopalkrishnashetty Sreenivasmurthy

  4. School of Medicine, Sun Yat-sen University (Shenzhen), Shenzhen, 518107, China

    Rong-biao Pi

  5. Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Ju-xian Song

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Contributions

JXS, AI, and ML designed the research; XJG, AI, JL, BCKT, ZZ, CFS, YXK, and SGS and performed the main experiments; XJG, AI, KJL, and ZQD analyzed the data; XJG, ZQD, and JXS wrote the paper; XJG, ZZ, SGS, CPKC, KHC, RBP, ZQD, JXS, and ML revised the paper; JXS and ML supervised the study.

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Correspondence to Ashok Iyaswamy, Ju-xian Song or Min Li.

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Guan, Xj., Deng, Zq., Liu, J. et al. Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer’s disease models. Acta Pharmacol Sin 45, 900–913 (2024). https://doi.org/10.1038/s41401-023-01197-1

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