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Lookup NU author(s): Professor Alan ThomasORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© The Author(s) 2024.Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer’s disease (AD) and offer many advantages over nonhuman models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer’s disease (AD) reflect clinical markers, including β-amyloid (Aβ) 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 Aβ 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.
Author(s): Rowland HA, Miller G, Liu Q, Li S, Sharp NR, Ng B, Wei T, Arunasalam K, Koychev I, Hedegaard A, Ribe EM, Chan D, Chessell T, Kocagoncu E, Lawson J, Malhotra P, Ridha BH, Rowe JB, Thomas AJ, Zamboni G, Zetterberg H, Cader MZ, Wade-Martins R, Lovestone S, Nevado-Holgado A, Kormilitzin A, Buckley NJ
Publication type: Article
Publication status: Published
Journal: Stem Cells
Year: 2025
Volume: 43
Issue: 3
Print publication date: 01/03/2025
Online publication date: 20/12/2024
Acceptance date: 03/09/2024
Date deposited: 08/04/2025
ISSN (print): 1066-5099
ISSN (electronic): 1549-4918
Publisher: Oxford University Press
URL: https://doi.org/10.1093/stmcls/sxae085
DOI: 10.1093/stmcls/sxae085
Data Access Statement: The data underlying this article will be shared on reasonable request to the corresponding authors.
PubMed id: 39704342
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