iPSC-Astrocyte morphology reflects patient clinical markers

Human iPSCs provide powerful cellular models of Alzheimers disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimers disease (AD) reflect clinical markers, including {beta}-amyloid (A{beta}) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous A{beta} oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/548687v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1df3486org.highwire.dtl.DTLVardef@f184d8org.highwire.dtl.DTLVardef@48a33dorg.highwire.dtl.DTLVardef@d53a90_HPS_FORMAT_FIGEXP M_FIG C_FIG