ABSTRACT
BACKGROUND: DNA topoisomerase IIß (topo IIß) plays a crucial role in neural differentiation and axonogenesis. Inhibition of topo IIß 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 IIß in the pathogenesis of AD remains to be elucidated. OBJECTIVES: We aimed to investigate the role of topo IIß 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-ß 1-42 (Aß1-42) for 48 hours with cultured cerebellar granule neurons (CGNs) isolated from post-natal eight-day rats. The regulatory role of topo IIß on the transcription of Nurr1 was analyzed in topo IIß silenced CGNs, and also topo IIß silenced and overexpressed in a neurally-differentiated human mesenchymal (hMSC) cell line. RESULTS: Aß1-42 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 IIß 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 IIß deficiency, and was increased in topo IIß overexpressing hMSCs. CONCLUSION: Our findings suggest that topo IIß 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 IIß with AD.
