Identification of a novel BACE1 inhibitor, timosaponin A-III, for treatment of Alzheimer's disease by a cell extraction and chemogenomics target knowledgebase-guided method.
Phytomedicine
; 75: 153244, 2020 May 24.
Article
em En
| MEDLINE
| ID: mdl-32502824
ABSTRACT
BACKGROUND:
Rhizoma Anemarrhenae (RA) has been conventionally used for treatment of Alzheimer's disease (AD) in Traditional Chinese Medicine, and thus, the active components from RA can be screened.PURPOSE:
This research aimed to identify the active components of RA and their targets and further clarify the molecular mechanisms underlying its anti-AD activity.METHODS:
First, the potential active compounds from RA were screened by neurocyte extraction and micro-dialysis methods. Second, the potential targets were predicted by a chemogenomics target knowledgebase and further explored by surface plasmon resonance and enzyme activity assays. Third, the pharmacological effects were evaluated by employing APP/PS1 transgenic mice and SH-SY5Y-APP cells. ELISAs and Western blot analyses were used to evaluate the expression of key molecules in the amyloidogenic and NMDAR/ERK pathways.RESULTS:
Timosaponin A-III (TA-III) was screened and identified as a potential active component for the anti-AD activity, and BACE1 was proven to be a potential high-affinity target. Enzyme kinetic analysis showed that TA-III had strong noncompetitive inhibitory activity against BACE1. The in vitro and in vivo assays indicated that TA-III had pharmacological effects through improving memory impairment, reducing Aß aggregation via the amyloidogenic pathway and preventing neuronal impairment through downregulating the NMDAR/ERK signaling pathway.CONCLUSION:
TA-III targets BACE1 to reduce Aß aggregation through down-regulating the NMDAR/ERK pathway for treating AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article