TY - JOUR
T1 - Bromo-protopine, a novel protopine derivative, alleviates tau pathology by activating chaperone-mediated autophagy for Alzheimer’s disease therapy
AU - Sreenivasmurthy, Sravan Gopalkrishnashetty
AU - Iyaswamy, Ashok
AU - Krishnamoorthi, Senthilkumar
AU - Reddi, Rambabu N.
AU - Kammala, Ananth Kumar
AU - Vasudevan, Karthick
AU - Senapati, Sanjib
AU - Zhu, Zhou
AU - Su, Cheng Fu
AU - Liu, Jia
AU - Guan, Xin Jie
AU - Chua, Ka Kit
AU - Cheung, King Ho
AU - Chen, Hubiao
AU - Zhang, Hong Jie
AU - Zhang, Yuan
AU - Song, Ju Xian
AU - Kumar Durairajan, Siva Sundara
AU - Li, Min
N1 - Funding Information:
This study was supported by the Innovation Technology Fund (ITS/187/13), Hong Kong Health and Medical Research Fund (HMRF/15163481, HMRF/17182541, HMRF/17182551, HMRF/09203776) and the Hong Kong General Research Fund (HKBU 12100618) from Hong Kong Government. The study was partly supported by the Research Fund from Hong Kong Baptist University (HKBU/RC-IRCs/17-18/03, IRCMS/19-20/H02), and partly supported by the National Natural Science Foundation of China (NSFC 81703487, NSFC 81773926) and Basic Research Fund from Shenzhen Science and Technology Program (JCYJ20180507184656626, JCYJ20180302174028790).
Publisher Copyright:
© 2022 Sreenivasmurthy, Iyaswamy, Krishnamoorthi, Reddi, Kammala, Vasudevan, Senapati, Zhu, Su, Liu, Guan, Chua, Cheung, Chen, Zhang, Zhang, Song, Kumar Durairajan and Li.
PY - 2022/10/26
Y1 - 2022/10/26
N2 - 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.
AB - 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.
KW - 3xTg-AD
KW - Alzheimer’s disease
KW - chaperone-mediated autophagy
KW - HDAC6
KW - P301S tau
KW - PRO-Br
UR - http://www.scopus.com/inward/record.url?scp=85141629590&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2022.1030534
DO - 10.3389/fmolb.2022.1030534
M3 - Journal article
AN - SCOPUS:85141629590
SN - 2296-889X
VL - 9
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
M1 - 1030534
ER -