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.
| Original language | English |
|---|---|
| Article number | 7 |
| Journal | Journal of Neuroinflammation |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2024 |
| Externally published | Yes |
Funding
The authors acknowledge the technical and scientific assistance of Sydney Microscopy & Microanalysis, the University of Sydney node of Microscopy Australia, as well as Sydney Analytical, a core research Facility at the University of Sydney, and the Sydney Informatics Hub. We also would like to acknowledge the NYSCF and Cedars-Sinai Medical Center's David and Janet Polak Foundation Stem Cell Core Laboratory providing the iPSC lines used within the study. The authors’ research is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1132524). M.K is an NHMRC Principal Research Fellow (APP1154692).
| Funders | Funder number |
|---|---|
| New York Stem Cell Foundation | |
| University of Sydney | |
| Cedars-Sinai Medical Center | |
| National Health and Medical Research Council | APP1132524, 1132524 |
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