Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome
Year: 2021
Type: article
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 R47H het TREM2 variant, common variant (Cv) or an R47H hom 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.
Source: Scientific Reports
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,990
Funders: European Federation of Pharmaceutical Industries and Associations, Parkinson's UK, European Commission, Rosetrees Trust, Eisai, Innovative Medicines Initiative, Directorate for Biological Sciences, University of California, Irvine, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G100154322, G1268142771, G1854469666, Using genetic variability in whole transcriptome expression in cells and tissues to understand the pathogenesis of Parkinson's and Alzheimer's disease, G3327757157, G434337789, G5130063062, London Interdisciplinary Doctoral Programme, Risk and Modifying factors in Fronto Temporal Dementia, UKDP: Integrated DEmentiA research environment (IDEA), G7809951108, G7979393549, Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study, Inflammation and AD: modulating microglia function focussing on TREM2 and CD33 - Sofia ref.: 115976, G830246384
OpenAlex ID: W3174414398