Astragaloside IV, a Natural PPARγ Agonist, Reduces Aß Production in Alzheimer's Disease Through Inhibition of BACE1.
Mol Neurobiol
; 54(4): 2939-2949, 2017 05.
Article
in En
| MEDLINE
| ID: mdl-27023226
ABSTRACT
A number of epidemiological studies have established a link between Alzheimer's disease (AD) and diabetes mellitus (DM). So, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the treatment of AD. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified herbal extract with a small molecular, astragaloside IV (AS-IV), as a selective PPARγ natural agonist in nervous cells by developing a PPAR-PPRE pathway regulatory system. Cultured SH-SY5Y cells transfected with pEGFP-N1-BACE1 were treated with AS-IV for 24 h or AS-IV plus the PPAR-γ antagonist GW9662 in vitro. APP/PS1 mice were intragastrically treated with AS-IV or AS-IV plus the GW9662 every 48 h for 3 months. Immunofluorescence, western blotting, and real-time PCR were used to examine the expression of PPARγ and BACE1. Immunohistochemical staining was performed to analyze the distribution of Aß plaques in the APP/PS1 mouse brain. The levels of Aß were determined using ELISA kits. AS-IV was shown to be a PPARγ agonist by establishing a high-throughput screening model for PPARγ agonists. The results showed that AS-IV treatment increased activity of PPARγ and inhibited BACE1 in vitro. As a result, Aß levels decreased significantly. GW9662, which is a PPARγ antagonist, significantly blocked the beneficial role of AS-IV. In vivo, AS-IV treatment increased PPARγ and BACE1 expression and reduced neuritic plaque formation and Aß levels in the brains of APP/PS1 mice. These effects of AS-IV could be effectively inhibited by GW9662. These results indicate that AS-IV may be a natural PPARγ agonist that suppressed activity of BACE1 and ultimately attenuates generation of Aß. Therefore, AS-IV may be a promising agent for modulating Aß-related pathology in AD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Saponins
/
Triterpenes
/
Amyloid beta-Peptides
/
Aspartic Acid Endopeptidases
/
PPAR gamma
/
Amyloid Precursor Protein Secretases
/
Alzheimer Disease
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Neurobiol
Journal subject:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Year:
2017
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA