A human embryonic stem cell model of A{beta}-dependent chronic progressive neurodegeneration

We describe construction and phenotypic analysis of a human embryonic stem cell model of progressive A?-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?40 or A?42, eliminating the need for amyloidogenic APP proteolysis. Following neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A?, 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?42 relative to A?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?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? to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.