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Graphene Oxide Attenuates Toxicity of Amyloid-β Aggregates in Yeast by Promoting Disassembly and Boosting Cellular Stress Response

ABSTRACT: Alzheimer’s disease (AD) is the most common form of neurodegenerations, with oligomerization and aggregation of amyloid-β peptides (Aβ) being one of its histopathological hallmarks. Recently, graphene oxide (GO) nanoflakes have attracted significant attention in biomedical fields by suppression of protein aggregation in vitro. However, the impact of GO on aggregated proteins in vivo is poorly understood. In earlier work, we developed a humanized AD model in yeast Saccharomyces cerevisiae by constitutively expressing Aβ42 peptides to mimic the chronic cytotoxicity during AD progression. Here we apply this in vivo model system to investigate the impact of GO on Aβ42 aggregates and cytotoxicity.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Vaishnavi Ravikumar

LAB HEAD: Ivan Mijakovic

PROVIDER: PXD029382 | Pride | 2023-09-28

REPOSITORIES: Pride

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			Action	DRS
	20210526_CO_1000IvMi_R01_1.raw	Raw
	20210526_CO_1000IvMi_R01_2.raw	Raw
	20210526_CO_1000IvMi_R01_3.raw	Raw
	20210526_CO_1000IvMi_R02_1.raw	Raw
	20210526_CO_1000IvMi_R02_2.raw	Raw

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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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Graphene Oxide Attenuates Toxicity of Amyloid-β Aggregates in Yeast by Promoting Disassembly and Boosting Cellular Stress Response

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