title: Cellular Model of Alzheimer's Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression.
abstract: DNA topoisomerase IIβ (topo IIβ) plays a crucial role in neural differentiation and axonogenesis. Inhibition of topo IIβ activity in vitro and in vivo results in shorter axons and increased DNA damage. These molecular events also involve in Alzheimer's disease (AD); however, the role of topo IIβ in the pathogenesis of AD remains to be elucidated.
  
  
  
  We aimed to investigate the role of topo IIβ association with Nuclear receptor related 1 protein (Nurr1) in the onset of AD.
  
  
  
  In vitro AD model was established by the incubation of fibrillar amyloid-β 1-42 (Aβ1-42) for 48 hours with cultured cerebellar granule neurons (CGNs) isolated from post-natal eight-day rats. The regulatory role of topo IIβ on the transcription of Nurr1 was analyzed in topo IIβ silenced CGNs, and also topo IIβ silenced and overexpressed in a neurally-differentiated human mesenchymal (hMSC) cell line.
  
  
  
  Aβ1-42 fibrils led to the upregulation of Presenilin1 and Cofilin1 genes as measured at mRNA levels and hyperphosphorylation of tau protein, all are distinctive characteristics of AD pathology. A significant decrease in topo IIβ expression at mRNA and protein levels and Nurr1 at mRNA level was also observed. In both cell types, Nurr1 expression was dramatically down-regulated due to topo IIβ deficiency, and was increased in topo IIβ overexpressing hMSCs.
  
  
  
  Our findings suggest that topo IIβ could be a down-stream target of signaling pathways contributing to AD-like pathology. However, further studies must be carried out in vivo to elucidate the precise association topo IIβ with AD.
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey.
authors.forename: Sule
authors.initials: S
authors.lastname: Terzioglu-Usak
authors.affiliation: Department of Medical Biochemistry, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey.
authors.forename: Yesim
authors.initials: Y
authors.lastname: Negis
authors.affiliation: Namık Kemal Street, No: 59/8., Avcılar, İstanbul 34310, Turkey.
authors.forename: Derya S
authors.initials: DS
authors.lastname: Karabulut
authors.affiliation: Ismetpasa Neighborhood., Tuna Street, No: 51, Bayrampasa, Istanbul 34040, Turkey.
authors.forename: Merve
authors.initials: M
authors.lastname: Zaim
authors.affiliation: Biotechnology Research Lab, EMC Technology Inc, ARGEM Building, Technocity, Avcılar, Istanbul 34320, Turkey.
authors.forename: Sevim
authors.initials: S
authors.lastname: Isik
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D009419:Nerve Tissue Proteins; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C075222:amyloid beta-protein (1-42); D004250:DNA Topoisomerases, Type II
keywords: Alzheimer's disease; DNA topoisomerase IIβ; amyloid beta 1-42 peptide; axonogenesis; human mesenchymal stem cell line; rat primary cerebellar
  granule neurons