Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells

Guoqiong Cao; Ping Su; Shuai Zhang; Limin Guo; Haijing Zhang; Yuexia Liang; Chunxia Qin; Wensheng Zhang

doi:10.1016/j.ejphar.2016.11.006

Ginsenoside Re reduces Aβ production by activating PPARγ to inhibit BACE1 in N2a/APP695 cells

Eur J Pharmacol. 2016 Dec 15:793:101-108. doi: 10.1016/j.ejphar.2016.11.006. Epub 2016 Nov 10.

Authors

Guoqiong Cao¹, Ping Su¹, Shuai Zhang¹, Limin Guo¹, Haijing Zhang¹, Yuexia Liang¹, Chunxia Qin¹, Wensheng Zhang²

Affiliations

¹ Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing 100088, China; Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing 100088, China; College of Resources Science Technology, Beijing Normal University, Beijing 100875, China.
² Beijing Area Major Laboratory of Protection and Utilization of Traditional Chinese Medicine, Beijing Normal University, Beijing 100088, China; Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Beijing 100088, China; College of Resources Science Technology, Beijing Normal University, Beijing 100875, China; National & Local United Engineering Research Center for Sanqi Resources Protection and Utilization Technology, Kunming 650000, China. Electronic address: [email protected].

PMID: 27840193
DOI: 10.1016/j.ejphar.2016.11.006

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition. Reducing the Aβ load may be a new perspective for AD treatment. Ginsenoside Re is an extract from Panax notoginseng, which is a well-known traditional Chinese medicine that has been used for the treatment of various diseases for years. Ginsenoside Re has been reported to decrease Aβ in Alzheimer's disease animal models, but the mechanism has not been fully elucidated. In the present study, we investigated the mechanism of ginsenoside Re. Our results showed that ginsenoside Re decreased the Aβ levels in N2a/APP695 cells. Aβ peptides are generated by β-secretase (β-site amyloid precursor protein cleaving enzyme 1 (BACE1)) and γ-secretase. We found that ginsenoside Re decreased the BACE1 mRNA and protein levels and inhibited BACE1 activity in the N2a/APP695 cells. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor that regulates the activity of the BACE1 promoter, and activating PPARγ can inhibit BACE1. The results also showed that ginsenoside Re significantly increased the PPARγ protein and mRNA levels. These effects of ginsenoside Re on BACE1 could be effectively inhibited by the PPARγ antagonist GW9662. These findings indicate that ginsenoside Re inhibits BACE1 through activation of PPARγ, which ultimately reduces the generation of Aβ_1-40 and Aβ_1-42. Therefore, ginsenoside Re may be a promising agent for the modulation of Aβ-related pathology in AD.

Keywords: Alzheimer´s disease; Aβ; BACE1; Ginsenoside Re; PPARγ.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / genetics
Amyloid beta-Peptides / biosynthesis*
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics*
Amyloid beta-Protein Precursor / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / genetics
Cell Line
Cell Survival / drug effects
Gene Expression Regulation / drug effects
Ginsenosides / pharmacology*
Humans
PPAR gamma / genetics
PPAR gamma / metabolism*
Peptide Fragments / biosynthesis*
Peptide Fragments / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Ginsenosides
PPAR gamma
Peptide Fragments
amyloid beta-protein (1-40)
amyloid beta-protein (1-42)
amyloid beta-protein precursor C-terminal fragment beta, human
ginsenoside Re
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human