title: The aqueous extract of Glycyrrhiza inflata can upregulate unfolded protein response-mediated chaperones to reduce tau misfolding in cell models of Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) and several neurodegenerative disorders known as tauopathies are characterized by misfolding and aggregation of tau protein. Although several studies have suggested the potential of traditional Chinese medicine (TCM) as treatment for neurodegenerative diseases, the role of TCM in treating AD and tauopathies have not been well explored.
  
  
  METHODS
  Tau protein was coupled to the DsRed fluorophore by fusing a pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) with DsRed. The ΔK280 tauRD-DsRed fusion gene was then used to generate Tet-On 293 and SH-SY5Y cell clones as platforms to test the efficacy of 39 aqueous extracts of TCM in reducing tau misfolding and in neuroprotection.
  
  
  RESULTS
  Seven TCM extracts demonstrated a significant reduction in tau misfolding and reactive oxidative species with low cytotoxicity in the ΔK280 tauRD-DsRed 293 cell model. Glycyrrhiza inflata and Panax ginseng also demonstrated the potential to improve neurite outgrowth in the ΔK280 tauRD-DsRed SH-SY5Y neuronal cell model. G. inflata further rescued the upregulation of ERN2 (pro-apoptotic) and downregulation of unfolded-protein-response-mediated chaperones ERP44, DNAJC3, and SERP1 in ΔK280 tauRD-DsRed 293 cells.
  
  
  CONCLUSIONS
  This in vitro study provides evidence that G. inflata may be a novel therapeutic for AD and tauopathies. Future applications of G. inflata on animal models of AD and tauopathies are warranted to corroborate its effect of reducing misfolding and potential disease modification.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Chang
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: I-Cheng
authors.initials: IC
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
authors.forename: Hsuan-Yuan
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
authors.forename: Hsuan-Chiang
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
authors.forename: Te-Hsien
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Weng
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Chao
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Yih-Ru
authors.initials: YR
authors.lastname: Wu
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
authors.forename: Jung-Yaw
authors.initials: JY
authors.lastname: Lin
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China.
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D006035:Glycyrrhiza / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008516:Medicine, Chinese Traditional; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D058767:Protein Unfolding / Q000187:drug effects*; D013329:Structure-Activity Relationship; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D014867:Water / Q000737:chemistry; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004365:Drugs, Chinese Herbal; C054369:MAPT protein, human; D018832:Molecular Chaperones; D010936:Plant Extracts; D016875:tau Proteins; D014867:Water
keywords: Alzheimer’s disease; G. inflata; TCM extracts; UPR-mediated chaperones; tau misfolding; tauopathy