2. Academic Validation
  3. PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer's Disease Defects By Inducing Autophagy in Mice Models

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

  • J Neuroimmune Pharmacol. 2023 Sep;18(3):509-528. doi: 10.1007/s11481-023-10083-w.
Senthilkumar Krishnamoorthi # 1 2,  Ashok Iyaswamy # 1 3 4,  Sravan Gopalkrishnashetty Sreenivasmurthy # 1 5,  Abhimanyu Thakur # 6,  Karthick Vasudevan 7,  Gaurav Kumar 8,  Xin-Jie Guan 1 4,  Kejia Lu 1 4,  Isha Gaurav 1,  Cheng-Fu Su 1 4,  Zhou Zhu 1 4,  Jia Liu 1 4,  Yuxuan Kan 1,  Selvaraj Jayaraman 9,  Zhiqiang Deng 1 4,  Ka Kit Chua 1 4,  King-Ho Cheung 1 4,  Zhijun Yang 1,  Ju-Xian Song 10,  Min Li 11 12
Affiliations

Affiliations

  • 1 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong , SAR, China.
  • 2 Centre for Trans-disciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India.
  • 3 Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, India.
  • 4 Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China.
  • 5 Department of Neurology, The University of Texas Medical Branch, Galveston, TX, USA.
  • 6 Pritzker School of Molecular Engineering, Ben May Department for Cancer Research, The University of Chicago, Illinois, USA.
  • 7 Department of Biotechnology, REVA University, Bangalore, India.
  • 8 Department of Clinical Research, School of Biological and Biomedical Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India.
  • 9 Centre of Molecular Medicine, Department of Biochemistry, Saveetha Dental College and Hospitals, Chennai, Tamil Nadu, India.
  • 10 Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 11 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong , SAR, China. [email protected].
  • 12 Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 37682502 DOI: 10.1007/s11481-023-10083-w
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.

Keywords

Alzheimer’s disease (AD); Amyloid beta (Aβ); Autophagy-lysosomal pathway (ALP); Caudatin; Peroxisome proliferator-activated receptor alpha (PPARα); Phospho-Tau.

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