Changes in iPSC-astrocyte morphology reflect Alzheimer’s disease patient clinical markers
Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's 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 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.
Authors
- Simon Lovestone (ORCID: https://orcid.org/0000-0003-0473-4565)
- Bryan Ng (ORCID: https://orcid.org/0000-0002-6819-0176)
- Ivan Koychev (ORCID: https://orcid.org/0000-0001-6813-8493)
- Georgina Miller
- Tharani Chessell
- James Benedict Rowe (ORCID: https://orcid.org/0000-0001-7216-8679)
- Kanisa Arunasalam
- Paresh Malhotra (ORCID: https://orcid.org/0000-0002-1897-0780)
- Richard Wade‐Martins (ORCID: https://orcid.org/0000-0001-6691-580X)
- Dennis Chan (ORCID: https://orcid.org/0000-0003-2089-1501)
- M. Zameel Cader (ORCID: https://orcid.org/0000-0002-6952-406X)
- Basil H. Ridha (ORCID: https://orcid.org/0000-0002-8850-9922)
- Giovanna Zamboni (ORCID: https://orcid.org/0000-0002-6133-3373)
- Noel J. Buckley (ORCID: https://orcid.org/0000-0003-1152-0653)
- Alan Thomas (ORCID: https://orcid.org/0000-0002-6667-9533)
- Elena M. Ribé (ORCID: https://orcid.org/0000-0003-2854-2576)
- Helen Rowland (ORCID: https://orcid.org/0009-0002-4735-8635)
- Alejo Nevado‐Holgado (ORCID: https://orcid.org/0000-0001-9276-2720)
- Nicola R Sharp
- Liting Wei (ORCID: https://orcid.org/0000-0002-7552-1834)
- Jennifer Lawson (ORCID: https://orcid.org/0000-0003-2637-7546)
- Ece Kocagöncü (ORCID: https://orcid.org/0000-0002-6292-7472)
- Andrey Kormilitzin (ORCID: https://orcid.org/0000-0003-3555-9181)
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Anne Hedegaard (ORCID: https://orcid.org/0000-0003-1536-896X)
- Qiang Liu (ORCID: https://orcid.org/0000-0002-7668-6868)
- Shuhan Li (ORCID: https://orcid.org/0000-0003-2461-7606)
Institutions
- AstraZeneca (United Kingdom) (GB)
- Agency for Science, Technology and Research (SG)
- University of Modena and Reggio Emilia (IT)
- University of Wisconsin–Madison (US)
- King's College London (GB)
- MRC Cognition and Brain Sciences Unit (GB)
- University of Cambridge (GB)
- Sahlgrenska University Hospital (SE)
- Nuffield Orthopaedic Centre (GB)
- Charing Cross Hospital (GB)
- University of Bristol (GB)
- University of Oxford (GB)
- Clinical Research Institute (US)
- Singapore Institute for Clinical Sciences (SG)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- AstraZeneca (Australia) (AU)
- Janssen (United Kingdom) (GB)
- UK Dementia Research Institute (GB)
- Oxford BioMedica (United Kingdom) (GB)
- AstraZeneca (Spain) (ES)
- National Hospital for Neurology and Neurosurgery (GB)
- Institute of Neurobiology (BG)
- University College London (GB)
- Imperial College London (GB)
- University of Newcastle Australia (AU)
- Newcastle University (GB)
- University of Gothenburg (SE)
- Medical Research Council (GB)
Publication Details
- Journal
- Stem Cells
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1093/stmcls/sxae085
- Citations
- 3
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Familjen Erling-Perssons Stiftelse
- Stiftelsen för Gamla Tjänarinnor
- EU Joint Programme – Neurodegenerative Disease Research
- European Federation of Pharmaceutical Industries and Associations
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- Department of Health and Social Care
- Imperial College London
- University College London
- European Commission
- Agency for Science, Technology and Research
- Hjärnfonden
- Vetenskapsrådet
- UK Dementia Research Institute
- Dementias Platform UK
- HORIZON EUROPE Framework Programme
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre