title: The Potential of Indole/Indolylquinoline Compounds in Tau Misfolding Reduction by Enhancement of HSPB1.
abstract: BACKGROUND
  Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons.
  
  
  METHODS
  We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection.
  
  
  RESULTS
  Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tauRD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tauRD-DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity.
  
  
  CONCLUSIONS
  Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Hsuan-Chiang
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Shu-Ling
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Te-Hsien
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chintakunta
authors.initials: C
authors.lastname: Ramesh
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Hon-Chung
authors.initials: HC
authors.lastname: Fung
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan.
authors.forename: Hei-Jen
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Hsiu Mei
authors.initials: HM
authors.lastname: Hsieh-Li
authors.affiliation: Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ching-Fa
authors.initials: CF
authors.lastname: Yao
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D000077191:Wortmannin; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007211:Indoles; D008164:Luminescent Proteins; D008301:Maleimides; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C413663:fluorescent protein 583; D016875:tau Proteins; C030374:indole; D007041:Hypoxanthine Phosphoribosyltransferase; C070515:bisindolylmaleimide I; D000077191:Wortmannin
keywords: Alzheimer's disease; HSPB1; Indole/indolylquinoline compounds; Tau misfolding; Therapeutics