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PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer’s Disease Defects By Inducing Autophagy in Mice Models

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Abstract

The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aβ and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP.

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Any raw data related to this manuscript may be requested from the corresponding author.

Code availability

All data in this study were statistically analyzed using GraphPad Prism software. All the figures were prepared using Adobe Illustrator. Graphical abstract was prepared using BioRender and Adobe Illustrator.

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Acknowledgements

We thank Dr. Carol Chu for her enormous support in ordering reagents and managing our lab needs. We thank Venkatapathy Kaliamoorthy and Tsz Yan Fung from School of Chinese medicine, HKBU for helping in staining and immunoblot experiments. We thank Ziwan Ning from School of Chinese medicine, HKBU for helping in pharmacokinetics analysis. We also thank Dr. Martha Dahlen for her English editing of this manuscript.

Funding

This present study was funded and supported by the grants of Health and Medical Research Fund (HMRF/17182541, HMRF/17182551, HMRF/19200721) and Research Grants Council of Hong Kong, the General Research Fund (GRF/HKBU 12100618) from Hong Kong Government and research grants from Hong Kong Baptist University (HKBU/RC-IRCs/17–18/03, IRCMS/19-20/H02), also research grants was supported by the National Natural Science Foundation of China (NSFC 81703487, NSFC 81773926) and Shenzhen Science and Technology Innovation Commission (JCYJ20180302174028790, JCYJ20180507184656626).

Author information

Author notes

  1. Senthilkumar Krishnamoorthi, Ashok Iyaswamy, Sravan Gopalkrishnashetty Sreenivasmurthy and Abhimanyu Thakur contributed equally to this work.

Authors and Affiliations

  1. School of Chinese Medicine, Hong Kong Baptist University, Hong Kong , SAR, China

    Senthilkumar Krishnamoorthi, Ashok Iyaswamy, Sravan Gopalkrishnashetty Sreenivasmurthy, Xin-Jie Guan, Kejia Lu, Isha Gaurav, Cheng-Fu Su, Zhou Zhu, Jia Liu, Yuxuan Kan, Zhiqiang Deng, Ka Kit Chua, King-Ho Cheung, Zhijun Yang & Min Li

  2. Centre for Trans-disciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India

    Senthilkumar Krishnamoorthi

  3. Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, India

    Ashok Iyaswamy

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

    Ashok Iyaswamy, Xin-Jie Guan, Kejia Lu, Cheng-Fu Su, Zhou Zhu, Jia Liu, Zhiqiang Deng, Ka Kit Chua, King-Ho Cheung & Min Li

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

    Sravan Gopalkrishnashetty Sreenivasmurthy

  6. Pritzker School of Molecular Engineering, Ben May Department for Cancer Research, The University of Chicago, Illinois, USA

    Abhimanyu Thakur

  7. Department of Biotechnology, REVA University, Bangalore, India

    Karthick Vasudevan

  8. Department of Clinical Research, School of Biological and Biomedical Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India

    Gaurav Kumar

  9. Centre of Molecular Medicine, Department of Biochemistry, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India

    Selvaraj Jayaraman

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

    Ju-Xian Song

Authors
  1. Senthilkumar Krishnamoorthi
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  2. Ashok Iyaswamy
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  3. Sravan Gopalkrishnashetty Sreenivasmurthy
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  4. Abhimanyu Thakur
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  5. Karthick Vasudevan
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  6. Gaurav Kumar
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  7. Xin-Jie Guan
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  8. Kejia Lu
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  9. Isha Gaurav
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  10. Cheng-Fu Su
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  11. Zhou Zhu
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  12. Jia Liu
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  13. Yuxuan Kan
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  14. Selvaraj Jayaraman
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  15. Zhiqiang Deng
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  16. Ka Kit Chua
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  17. King-Ho Cheung
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  18. Zhijun Yang
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  19. Ju-Xian Song
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  20. Min Li
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Contributions

The research study was conceived and conceptualized by: AI and ML. Methodology: AI, SKK, SGS, VK, TYF, ZD, ZZ, CFS, JL, AT, IG, GK, XJG, ZJY, YXK. Investigation: AI, SKK, VK, SGS, AT. Data curation: AI, SKK, SGS, VK, GK, AT. Writing original draft: AI, SKK, SGS, AT and ML. Writing, reviewing, and editing: ZZ, CFS, JL, KL, XJG, IG, GK, ZJY, YXK, ZD, ML, JXS and KHC. Funding acquisition: AI and ML. Resources: ML. All authors read and approved the final manuscript.

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Correspondence to Min Li.

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The research protocols and animal behavior experiments in this research were approved by the Research Committee of Hong Kong Baptist University for the Use of Human and Animal Subjects in Research and Teaching (HASC) (#HASC/18-19). The animal handling and experiments were performed with approved animal license (20-27) in DH/HT&A/8/2/6 Pt.1. In this study only mouse models were used for the experiments.

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Krishnamoorthi, S., Iyaswamy, A., Sreenivasmurthy, S.G. et al. PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer’s Disease Defects By Inducing Autophagy in Mice Models. J Neuroimmune Pharmacol 18, 509–528 (2023). https://doi.org/10.1007/s11481-023-10083-w

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