RRC ID 65060
Author Terzioglu-Usak S, Negis Y, Karabulut DS, Zaim M, Isik S.
Title Cellular Model of Alzheimer's Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression.
Journal Curr Alzheimer Res
Abstract BACKGROUND: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.
OBJECTIVES:We aimed to investigate the role of topo IIβ association with Nuclear receptor related 1 protein (Nurr1) in the onset of AD.
METHODS: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.
RESULTS: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.
CONCLUSION: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.
Volume 14(6)
Pages 636-644
Published 2017-1-1
DOI 10.2174/1567205014666170117103217
PMID 28124588
MeSH Amyloid beta-Peptides / pharmacology* Amyloidogenic Proteins / metabolism* Animals Animals, Newborn Cell Differentiation / drug effects Cells, Cultured Cerebellum / cytology DNA Topoisomerases, Type II / genetics DNA Topoisomerases, Type II / metabolism* Down-Regulation / drug effects* Down-Regulation / genetics Nerve Tissue Proteins / metabolism Neurons / drug effects* Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism* Peptide Fragments / pharmacology* RNA, Messenger / metabolism RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Rats Rats, Wistar
Human and Animal Cells UE7T-13(RCB2161)