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Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition
Sreenivasmurthy, Sravan Gopalkrishnashetty1; Iyaswamy, Ashok1; Krishnamoorthi, Senthilkumar1; Senapati, Sanjib2; Malampati, Sandeep1,3; Zhu, Zhou1; Su, Cheng Fu1; Liu, Jia1; Guan, Xin Jie1; Tong, Benjamin Chun Kit1,3; Cheung, King Ho1,3; Tan, Jie Qiong4; Lu, Jia Hong5; Durairajan, Siva Sundara Kumar6; Song, Ju Xian1,7; Li, Min1,3
Source PublicationPhytomedicine

Background: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD). Purpose: To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese). Study design: By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models. Methods: Liquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro. Results: Our pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS). Conclusion: We identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases.

Keyword3xtg-ad Mice Alzheimer's Disease Hdac6 P301s-tau Mice Phospho-tau Protopine
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Scopus ID2-s2.0-85121419828
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Personal research not belonging to the institution
Corresponding AuthorDurairajan, Siva Sundara Kumar; Song, Ju Xian; Li, Min
Affiliation1.Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, China
2.Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India
3.Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, China
4.Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
5.State Key Lab of Quality Research in Chinese Medicine, University of Macao, China
6.Mycobiology and Neurodegenerative Disease Research Laboratory, Department of Microbiology, Central University of Tamil Nadu, Thiruvarur, India
7.Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
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Sreenivasmurthy, Sravan Gopalkrishnashetty,Iyaswamy, Ashok,Krishnamoorthi, Senthilkumar,et al. Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition[J]. Phytomedicine,2022,96.
APA Sreenivasmurthy, Sravan Gopalkrishnashetty,Iyaswamy, Ashok,Krishnamoorthi, Senthilkumar,Senapati, Sanjib,Malampati, Sandeep,Zhu, Zhou,Su, Cheng Fu,Liu, Jia,Guan, Xin Jie,Tong, Benjamin Chun Kit,Cheung, King Ho,Tan, Jie Qiong,Lu, Jia Hong,Durairajan, Siva Sundara Kumar,Song, Ju Xian,&Li, Min.(2022).Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition.Phytomedicine,96.
MLA Sreenivasmurthy, Sravan Gopalkrishnashetty,et al."Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition".Phytomedicine 96(2022).
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