iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype
Abstract Background Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer’s disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morpholog...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-01-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02951-2 |
| _version_ | 1797363129776078848 |
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| author | Michael A. Sullivan Samuel D. Lane André D. J. McKenzie Sarah R. Ball Margaret Sunde G. Gregory Neely Cesar L. Moreno Alexandra Maximova Eryn L. Werry Michael Kassiou |
| author_facet | Michael A. Sullivan Samuel D. Lane André D. J. McKenzie Sarah R. Ball Margaret Sunde G. Gregory Neely Cesar L. Moreno Alexandra Maximova Eryn L. Werry Michael Kassiou |
| author_sort | Michael A. Sullivan |
| collection | DOAJ |
| description | Abstract Background Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer’s disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. Methods iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ42. Results AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. Conclusion Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a ‘primed’ phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ42 production and phagocytosis. |
| first_indexed | 2024-03-08T16:15:48Z |
| format | Article |
| id | doaj.art-ef7a844245764d02918279afb7d9cfa9 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-08T16:15:48Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ef7a844245764d02918279afb7d9cfa92024-01-07T12:37:17ZengBMCJournal of Neuroinflammation1742-20942024-01-0121112310.1186/s12974-023-02951-2iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotypeMichael A. Sullivan0Samuel D. Lane1André D. J. McKenzie2Sarah R. Ball3Margaret Sunde4G. Gregory Neely5Cesar L. Moreno6Alexandra Maximova7Eryn L. Werry8Michael Kassiou9School of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Life and Environmental Sciences, Faculty of Science, The University of SydneySchool of Life and Environmental Sciences, Faculty of Science, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Medical Sciences, The Faculty of Medicine and Health, The University of SydneySchool of Chemistry, The Faculty of Science, The University of SydneyAbstract Background Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer’s disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. Methods iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ42. Results AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. Conclusion Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a ‘primed’ phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ42 production and phagocytosis.https://doi.org/10.1186/s12974-023-02951-2MicrogliaAstrocytesGliaAlzheimer’s diseasePro-inflammatoryiPSC |
| spellingShingle | Michael A. Sullivan Samuel D. Lane André D. J. McKenzie Sarah R. Ball Margaret Sunde G. Gregory Neely Cesar L. Moreno Alexandra Maximova Eryn L. Werry Michael Kassiou iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype Journal of Neuroinflammation Microglia Astrocytes Glia Alzheimer’s disease Pro-inflammatory iPSC |
| title | iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype |
| title_full | iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype |
| title_fullStr | iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype |
| title_full_unstemmed | iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype |
| title_short | iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype |
| title_sort | ipsc derived psen2 n141i astrocytes and microglia exhibit a primed inflammatory phenotype |
| topic | Microglia Astrocytes Glia Alzheimer’s disease Pro-inflammatory iPSC |
| url | https://doi.org/10.1186/s12974-023-02951-2 |
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