Aberrant iPSC-derived human astrocytes in Alzheimer's disease.
The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.
The University of Central Lancashire, Preston PR1 2HE, UK.
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Jones
The University of Manchester, Manchester M13 9PT, UK.
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Atkinson-Dell
The University of Manchester, Manchester M13 9PT, UK.|Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao 48011, Spain.
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Verkhratsky
The University of Manchester, Manchester M13 9PT, UK.
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Mohamet
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D015415:Biomarkers; D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; D005974:Glutamate-Ammonia Ligase