The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells

https://doi.org/10.1016/j.bbrc.2015.12.025Get rights and content
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Highlights

  • Cellular Alzheimer's disease models that overexpressed mutant PS1 were established.

  • The overexpression of PS1 did not affect the undifferentiated status of hESCs.

  • The PS1 overexpression did not affect the neural differentiation ability of hESCs.

  • Increases in the Aβ42/Aβ40 and Aβ43/Aβ40 ratios were observed.

  • Synaptic dysfunction was observed in mutant PS1-expressing AD models.

Abstract

Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery.

Keywords

Human embryonic stem cell
Alzheimer's disease
Cellular disease model
Presenilin 1
Synaptic dysfunction

Abbreviations

hPSC
human pluripotent stem cell
hESC
human embryonic stem cell
hiPSC
human induced pluripotent stem cell
AD
Alzheimer's disease
PS1
presenilin 1
amyloid beta
ALS
amyotrophic lateral sclerosis
SOD1
superoxide dismutase 1
HPRT1
hypoxanthine phosphoribosyltransferase 1

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1

Current address. ReproCELL Inc., Yokohama, Kanagawa 222-0033, Japan.