Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer’s disease therapy

Sravan Gopalkrishnashetty Sreenivasmurthy, Ashok Iyaswamy, Senthilkumar Krishnamoorthi, Rambabu N. Reddi, Ananth Kumar Kammala, Karthick Vasudevan, Sanjib Senapati, Zhou Zhu, Cheng Fu Su, Jia Liu, Xin Jie Guan, Ka Kit Chua, King Ho Cheung, Hubiao Chen, Hong Jie Zhang, Yuan Zhang, Ju Xian Song, Siva Sundara Kumar Durairajan, Min Li

Research output: Contribution to journalArticlepeer-review

Abstract

Emerging evidence from Alzheimer’s disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of −8.4 kcal/mol and an IC50 value of 1.51 µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.

Original languageEnglish (US)
Article number1030534
JournalFrontiers in Molecular Biosciences
Volume9
DOIs
StatePublished - Oct 26 2022

Keywords

  • 3xTg-AD
  • Alzheimer’s disease
  • chaperone-mediated autophagy
  • HDAC6
  • P301S tau
  • PRO-Br

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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