title: Tripchlorolide Attenuates β-amyloid Generation via Suppressing PPARγ-Regulated BACE1 Activity in N2a/APP695 Cells.
abstract: Due to its apparent rate-limiting function, BACE1 (β-secretase) appears to be a prime target for prevention of amyloid-β (Aβ) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor binding site of the BACE1 promoter, indicating that PPARγ may be a potential target for AD treatment. Several studies have demonstrated that PPARγ activation is involved in the immunostimulation of amyloid-β precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T4), with a similar chemical structure to that of NSAIDs, decreased the levels of Aβ secreted in N2a-APP695 cells. T4treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPPβ, a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARγ from cytoplasm to nuclear. Intriguingly, T4, like pioglitazone (a PPARγ agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARγ antagonist). These results indicate that T4may 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 the generation of Aβ. Due to its capability to alter Aβ generation and to protect central neural system against the neurotoxicity of Aβ, T4may serve as a promising agent in modulating Aβ-related pathology in Alzheimer's disease.
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Chen
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Pan
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Yuan-Gui
authors.initials: YG
authors.lastname: Zhu
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Shi
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China. chenxc998@163.com.|Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China. chenxc998@163.com.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism*; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D004224:Diterpenes; D047495:PPAR gamma; D010616:Phenanthrenes; D012333:RNA, Messenger; C068051:tripchlorolide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Amyloid-β precursor protein; Amyloidogenesis; BACE1; N2a cells; PPARγ; Tripchlorolide