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

Senthilkumar Krishnamoorthi, Ashok Iyaswamy, Sravan Gopalkrishnashetty Sreenivasmurthy, Abhimanyu Thakur, Karthick Vasudevan, Gaurav Kumar, Xin-Jie Guan, Kejia Lu, Isha Gaurav, Cheng-Fu Su, Zhou Zhu, Jia Liu, Yuxuan Kan, Selvaraj Jayaraman, Zhiqiang Deng, Ka Kit Chua, King-Ho Cheung, Zhijun Yang, Ju-Xian Song, Min Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)509-528
Number of pages20
JournalJournal of NeuroImmune Pharmacology
Volume18
Issue number3
DOIs
Publication statusPublished - Sept 2023

Scopus Subject Areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

User-Defined 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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