Title:Cellular Model of Alzheimer's Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression
Volume: 14
Issue: 6
Author(s): Sule Terzioglu-Usak, Yesim Negis, Derya S. Karabulut, Merve Zaim and Sevim Isik*
Affiliation:
- Biotechnology Research Lab, EMC Technology Inc, ARGEM Building, Technocity, Avcılar, Istanbul 34320,Turkey
Keywords:
DNA topoisomerase IIβ, Alzheimer's disease, amyloid beta 1-42 peptide, axonogenesis, rat primary cerebellar
granule neurons, human mesenchymal stem cell line.
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.
