iPSC-Astrocyte morphology reflects patient clinical markers

Rowland, H. A.; Miller, G.; Liu, Q.; Sharp, N. R.; Ng, B.; Wei, T.; Arunasalam, K.; Koychev, I.; Hedegaard, A.; Ribe, E. M.; Chan, D.; Chessell, T.; Kocagoncu, E.; Lawson, J.; Malhotra, P. A.; Ridha, B. H.; Rowe, J. B.; Thomas, A. J.; Zamboni, G.; Zetterberg, H.; Cader, Z.; Wade-Martins, R.; Lovestone, S.; Nevado Holgado, A.; Kormilitzin, A.; Buckley, N. J.

doi:10.1101/2023.07.15.548687

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bioRxiv · 10.1101/2023.07.15.548687

iPSC-Astrocyte morphology reflects patient clinical markers

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Abstract

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

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Rowland, H. A., Miller, G., Liu, Q., Sharp, N. R., Ng, B., Wei, T., Arunasalam, K., Koychev, I., Hedegaard, A., Ribe, E. M., Chan, D., Chessell, T., Kocagoncu, E., Lawson, J., Malhotra, P. A., Ridha, B. H., Rowe, J. B., Thomas, A. J., Zamboni, G., Zetterberg, H., Cader, Z., Wade-Martins, R., Lovestone, S., Nevado Holgado, A., Kormilitzin, A., Buckley, N. J.. 2023-07-18. iPSC-Astrocyte morphology reflects patient clinical markers. https://doi.org/10.1101/2023.07.15.548687

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