Format

Send to

Choose Destination
Eur J Pharmacol. 2020 Mar 20;876:173065. doi: 10.1016/j.ejphar.2020.173065. [Epub ahead of print]

Significant combination of Aβ aggregation inhibitory and neuroprotective properties in silico, in vitro and in vivo by bis(propyl)-cognitin, a multifunctional anti-Alzheimer's agent.

Author information

1
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
2
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
3
Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.
4
Mayo Cancer Center, Department of Pharmacology, Mayo Clinic, Rochester, MN, USA.
5
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
6
Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
7
Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China; College of Biotechnology and National and Local United Engineering Lab of Metabolic Control Fermentation Technology, Tianjin University of Science & Technology, Tianjin, China. Electronic address: fufengliu@tust.edu.cn.
8
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Electronic address: linzx@cuhk.edu.hk.
9
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. Electronic address: bcyfhan@polyu.edu.hk.

Abstract

Inhibition of Aβ aggregation and neurotoxicity has been developed as an attractive therapeutic strategy to combat Alzheimer's disease (AD). Bis(propyl)-cognitin (B3C) is a multifunctional dimer derived from tacrine. Herein, the anti-aggregation and disassembly effects of B3C on Aβ, together with the neuroprotective effects and underlying mechanisms of B3C against Aβ-induced neurotoxicity were investigated in silico, in vitro and in vivo. Data from Thioflavin-T fluorescence and atomic force microscopy assays indicated that B3C (1-10 μM), but not its monomer tacrine, greatly inhibited the formation of Aβ fibrils and disaggregated pre-formed mature Aβ fibrils. Comparative molecular dynamics simulation results revealed a possible binding mode that prevented Aβ fibrils formation, showing that B3C favorably bound to Aβ via hydrophobic interactions. Additionally, B3C was able to block the neurotoxicity caused by Aβ fibrils in cultured PC12 cells. Very encouragingly, B3C (0.3 and 0.45 mg/kg) markedly alleviated the cognitive impairments in rats insulted by intra-hippocampal injection of Aβ1-42 fibrils, more potently than tacrine (1 and 2 mg/kg). Furthermore, mechanistic studies demonstrated that B3C reversed the inhibition of phospho-GSK3β at Ser9 site in vitro and in vivo caused by Aβ, suggesting the neuroprotection of B3C was achieved through the inhibition of GSK3β pathway. These findings indicate that B3C could serve as an effective inhibitor of Aβ aggregation and neurotoxicity, and provide novel molecular insights into the potential application of B3C in AD prevention and treatment.

KEYWORDS:

Alzheimer’s disease; Aβ aggregation and disaggregation; GSK3β pathway; Molecular dynamics simulation; Neuroprotection; bis(propyl)-cognitin

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center