Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome

Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome

Abstract The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom...

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Autores principales: Katharina Cosker, Anna Mallach, Janhavi Limaye, Thomas M. Piers, James Staddon, Stephen J. Neame, John Hardy, Jennifer M. Pocock
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:21e1387021654817b07d89b643d58caa2021-12-02T17:14:30ZMicroglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome10.1038/s41598-021-91207-12045-2322https://doaj.org/article/21e1387021654817b07d89b643d58caa2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91207-1https://doaj.org/toc/2045-2322Abstract The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.Katharina CoskerAnna MallachJanhavi LimayeThomas M. PiersJames StaddonStephen J. NeameJohn HardyJennifer M. PocockNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Katharina Cosker
Anna Mallach
Janhavi Limaye
Thomas M. Piers
James Staddon
Stephen J. Neame
John Hardy
Jennifer M. Pocock
Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
description Abstract The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.
format article
author Katharina Cosker
Anna Mallach
Janhavi Limaye
Thomas M. Piers
James Staddon
Stephen J. Neame
John Hardy
Jennifer M. Pocock
author_facet Katharina Cosker
Anna Mallach
Janhavi Limaye
Thomas M. Piers
James Staddon
Stephen J. Neame
John Hardy
Jennifer M. Pocock
author_sort Katharina Cosker
title Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
title_short Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
title_full Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
title_fullStr Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
title_full_unstemmed Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
title_sort microglial signalling pathway deficits associated with the patient derived r47h trem2 variants linked to ad indicate inability to activate inflammasome
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/21e1387021654817b07d89b643d58caa
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