title: Ginsenoside Rg1 attenuates β-amyloid generation via suppressing PPARγ-regulated BACE1 activity in N2a-APP695 cells.
abstract: 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 Aβ₁₋₄₀ and Aβ₁₋₄₂ 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.
authors.affiliation: Department of Neurology, Fujian Institute of Geriatrics, the Affiliated Union Hospital of Fujian Medical University, People's Republic of China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Lin
authors.forename: Yuan-Gui
authors.initials: YG
authors.lastname: Zhu
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002491:Central Nervous System Agents; D004365:Drugs, Chinese Herbal; D036145:Ginsenosides; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D010446:Peptide Fragments; D012333:RNA, Messenger; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C543304:amyloid beta-protein precursor C-terminal fragment beta, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C035054:ginsenoside Rg1