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Single-cell RNA sequencing of human iPSC-derived forebrain organoids following amyloid-β42 treatment, microglia co-culture, and maraviroc treatment

ABSTRACT: Human induced pluripotent stem cell (iPSC)-derived forebrain organoids were used to model Alzheimer's disease-associated pathology and investigate the effects of microglia co-culture and CCR5 inhibition. Day 60 forebrain organoids were assigned to four experimental groups: untreated control, amyloid-β42 (Aβ42)-treated, Aβ42-treated followed by co-culture with mature human iPSC-derived microglia, and Aβ42-treated followed by maraviroc treatment and co-culture with mature human iPSC-derived microglia. Single-cell RNA sequencing was performed using the MGI DNBelab C-TaiM4 platform to characterize transcriptional changes and cellular composition across the four experimental conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339602 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description: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 show 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.

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Single-cell RNA sequencing of human iPSC-derived forebrain organoids following amyloid-β42 treatment, microglia co-culture, and maraviroc treatment

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