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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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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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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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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DOI: https://doi.org/10.1038/s41401-023-01197-1