Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.08.288043v1?rss=1 Authors: Cosker, K., Mallach, A., Limaye, J., Piers, T. M., Staddon, J., Neame, S. J., Hardy, J., Pocock, J. M. Abstract: The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimers 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. Copy rights belong to original authors. Visit the link for more info