Ginsenoside Rg1 attenuates β-amyloid generation via suppressing PPARγ-regulated BACE1 activity in N2a-APP695 cells

• Published in: European journal of pharmacology 2012-01, Vol.675 (1), p.15-21
• Main Authors: Chen, Li-min, Lin, Zhi-ying, Zhu, Yuan-gui, Lin, Nan, Zhang, Jing, Pan, Xiao-dong, Chen, Xiao-chun
• Format: Article
• Language: English
• Subjects: agonists; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - secretion; Amyloid beta-Protein Precursor - antagonists & inhibitors; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Amyloidgenesis; Animal models; Animals; antagonists; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; BACE1; beta -Amyloid; beta -Site APP cleaving enzyme 1; binding sites; Brain; Cell Line; Central Nervous System Agents - pharmacology; cognition; Cognitive ability; Cytoplasm; Drugs, Chinese Herbal - pharmacology; Enzymes; Gene Expression Regulation - drug effects; Ginsenoside; ginsenosides; Ginsenosides - pharmacology; Humans; Memory; messenger RNA; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - secretion; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurons - secretion; Nuclear transport; Panax; patients; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - secretion; peptides; Peroxisome proliferator-activated receptors; pharmacology; pioglitazone; PPAR gamma - agonists; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; PPARγ; Promoter Regions, Genetic - drug effects; Promoters; Protein Transport - drug effects; Recombinant Proteins - metabolism; Recombinant Proteins - secretion; Regulatory sequences; RNA, Messenger - metabolism; therapeutics; Transcription factors; Translation; translation (genetics)
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.11.039

The level of β-site APP-cleaving enzyme 1 (BACE1) has been documented to increase in the brains of patients with Alzheimer's disease, which has resulted in elevation of β-amyloid (Aβ) peptides. As a transcription factor binding site of the BACE1 promoter, peroxisome proliferator–activated receptor-γ (PPARγ) response element regulates the activity of the BACE1 promoter activity, indicating that PPARγ may become a potential target for Alzheimer's disease treatment. Recent studies have demonstrated that ginsenoside Rg1 which is an effective component of extracts of ginseng can prevent memory loss and improve cognitive function in a variety of animal models. However, the underlying mechanism remains unclear. In the present study, we found that Rg1 decreased the levels of Aβ 1–40 and Aβ 1–42 secreted in N2a-APP695 cells. The expression levels of both BACE1 mRNA and protein as well as β-CTFs, a cleavaged C-terminal fragment of APP by BACE1, were reduced in cells treated with Rg1. Moreover, Rg1 treatment led to a translocation of PPARγ from cytoplasm to nuclear. Intriguingly, Rg1, like pioglitazone (a PPARγ agonist), suppressed BACE1 activity in N2a-APP695 cells, while its effect on BACE1 activity was attenuated by GW9662 (a PPARγ antagonist). These results indicate that Rg1 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate Aβ generation. Therefore, ginsenoside Rg1 may serve as a promising agent in modulating Aβ-related pathology in Alzheimer's disease.