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Fabrication of Amyloid-β-Secreting Alginate Microbeads for Use in Modelling Alzheimer's Disease
Published on: July 6, 2019
Cellular Model of Alzheimer's Disease: Aβ1-42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ
Sule Terzioglu-Usak1, Yesim Negis2, Derya S Karabulut3
1Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, 34093, Fatih, Istanbul, Turkey.
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.
Insights
DNA topoisomerase IIβ (topo IIβ) impacts Alzheimer's disease (AD) pathology. Reduced topo IIβ expression in AD models leads to decreased Nurr1, a key protein in neuronal function, suggesting topo IIβ is involved in AD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- DNA topoisomerase IIβ (topo IIβ) is vital for neural development and axon growth.
- Topo IIβ inhibition causes DNA damage and shorter axons.
- The role of topo IIβ in Alzheimer's disease (AD) pathogenesis is unclear.
Purpose of the Study:
- To investigate the role of topo IIβ in AD onset.
- To examine the association between topo IIβ and Nuclear receptor related 1 protein (Nurr1) in AD.
Main Methods:
- An in vitro AD model using cultured rat cerebellar granule neurons (CGNs) exposed to amyloid-β 1-42 (Aβ1-42) fibrils.
- Analysis of Nurr1 transcription regulation by topo IIβ in silenced and overexpressed cells (CGNs and human mesenchymal stem cells).
Main Results:
- Aβ1-42 fibrils induced AD hallmarks: increased Presenilin1 and Cofilin1 mRNA, and tau hyperphosphorylation.
- Significant decreases in topo IIβ and Nurr1 mRNA levels were observed.
- Topo IIβ deficiency down-regulated Nurr1 expression, while overexpression increased it.
Conclusions:
- Topo IIβ may be a downstream target in AD-related signaling pathways.
- Further in vivo studies are required to confirm the precise association between topo IIβ and AD.
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