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bioRxiv · 10.1101/419978

A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration

Ubina, T.·Magallanes, M.·Srivastava, S.·Warden, C.·Yee, J.-K.·Salvaterra, P. M.
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Abstract

We describe construction and phenotypic analysis of a human embryonic stem cell model of progressive A{beta}-dependent neurodegeneration (ND) with potential relevance to Alzheimers disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of A{beta}40 or A{beta}42, eliminating the need for amyloidogenic APP proteolysis. Following neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A{beta}, exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for A{beta}42 relative to A{beta}40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (DEGs) with similar directional fold change but larger absolute values in the A{beta}42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions are significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking A{beta} to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.

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Ubina, T., Magallanes, M., Srivastava, S., Warden, C., Yee, J.-K., Salvaterra, P. M.. 2018-09-17. A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration. https://doi.org/10.1101/419978

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