title: The potential of synthetic indolylquinoline derivatives for Aβ aggregation reduction by chemical chaperone activity.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular β-amyloid (Aβ) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aβ deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aβ aggregate reducers could be effective for AD treatment. Using a Trx-His-Aβ biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aβ aggregation. Treating Tet-On Aβ-GFP 293 cells with these compounds reduced Aβ aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aβ-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aβ-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aβ-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aβ-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Ya-Jen
authors.initials: YJ
authors.lastname: Chiu
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Te-Hsien
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Chi-Mei
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Chintakunta
authors.initials: C
authors.lastname: Ramesh
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Chung-Hsin
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Hon-Chung
authors.initials: HC
authors.lastname: Fung
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Jung-Yaw
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
authors.forename: Ching-Fa
authors.initials: CF
authors.lastname: Yao
authors.affiliation: Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei 11260, Taiwan.
authors.forename: Hei-Jen
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan. Electronic address: t43019@ntnu.edu.tw.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan. Electronic address: t43006@ntnu.edu.tw.
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan. Electronic address: hmhsieh@ntnu.edu.tw.
authors.forename: Hsiu Mei
authors.initials: HM
authors.lastname: Hsieh-Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011804:Quinolines; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; C037219:quinoline
keywords: Alzheimer's disease; Aβ aggregation; Synthetic indolylquinoline derivatives; Therapeutics