Excitatory neurons derived from human induced Pluripotent Stem Cells show transcriptomic differences in Alzheimers patients from controls

Abstract

The recent advances in creating pluripotent stem cells from somatic cells and differentiating them into a variety of cell types is allowing us to study them without the caveats associated with disease related changes. We have generated induced Pluripotent Stem Cells (iPSCs) from eight Alzheimers disease (AD) patients and six controls and used lentiviral delivery to differentiate them into excitatory glutamatergic neurons. We have performed RNA sequencing on these neurons and compared the Alzheimers and control transcriptomes. We find that 621 genes show differences in expression levels at adjusted p<0.05 between the case and control derived neurons. These genes show significant overlap and direction concordance with genes reported from a Single cell transcriptome study of Alzheimers patients, they contain 5 genes implicated with AD from genome wide association studies and they appear to be part of a larger functional network as indicated by an excess of interactions between them observed in the protein-protein interaction database STRING. Exploratory analysis with Uniform Manifold Approximation and Projection (UMAP) suggests distinct clusters of patients, based on gene expression, who maybe clinically different. If confirmed this finding will to contribute to precision medicine approaches to subgroup Alzheimers disease.