title: Astragaloside IV, a Natural PPARγ Agonist, Reduces Aβ Production in Alzheimer's Disease Through Inhibition of BACE1.
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 Aβ plaques in the APP/PS1 mouse brain. The levels of Aβ 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, Aβ 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 Aβ 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 Aβ. Therefore, AS-IV may be a promising agent for modulating Aβ-related pathology in AD.
authors.affiliation: Basic Medicine combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, 110847, Shenyang, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Basic Medicine combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, 110847, Shenyang, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, Mudanjiang Medical University, Mudanjiang, People's Republic of China.
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Hu
authors.affiliation: Subject consciousness of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, People's Republic of China.
authors.forename: Song
authors.initials: S
authors.lastname: Yu
authors.affiliation: Basic Medicine combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, 110847, Shenyang, People's Republic of China.
authors.forename: Bao-Kun
authors.initials: BK
authors.lastname: Li
authors.affiliation: Basic Medicine combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, 110847, Shenyang, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Subject consciousness of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ren
authors.affiliation: Basic Medicine combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, 110847, Shenyang, People's Republic of China. zhanglide99@126.com.
authors.forename: Li-De
authors.initials: LD
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D058225:Plaque, Amyloid / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D047495:PPAR gamma; D053764:Presenilin-1; D012503:Saponins; D014315:Triterpenes; C052064:astragaloside A; D008156:Luciferases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Astragaloside IV; BACE1; PPARγ