APP Swedish mutation affects human iPSC-derived pericyte-like cells.

The APP Swedish (APPswe) mutation causes a familial form of Alzheimer’s disease (AD). While vascular dysfunction is commonly observed in AD and potentially linked to disease progression, the specific contributions of vascular cell types, particularly pericytes, are unclear. Pericytes are mural cells that wrap around endothelial cells in capillaries and play a critical role in modulating vascular functions. We have observed altered functionality in pericyte-like cells with the APPswe mutation, including compromised barrier maintenance, reduced angiogenesis support, increased secretion of pro-inflammatory cytokines upon stimulation, and a hypercontractility phenotype.To further investigate these changes, we aim to analyze gene expression at the transcriptomic level and explore pathway alterations. We harvested cultures from iPSC-derived pericyte-like cells from seven healthy control lines and three APPswe lines and conducted bulk RNA sequencing. We then performed analyses including identifying differentially expressed genes (DEGs) and pathway analysis. Our results revealed significant activation of the cytoskeleton/actin pathway and hypercontractile proteins in APPswe pericyte-like cells, which likely contribute to the observed hypercontractility phenotype. Additionally, we identified DEGs and pathways associated with angiogenesis, metabolism, and inflammation, potentially explaining the changes observed in APPswe cells.Overall, the RNA sequencing data from our study highlight potential pathways through which pericytes may contribute to vascular dysfunction and disease progression in AD.