Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia.

Nature Neuroscience
Benjamin J AndreoneJoseph W Lewcock

Abstract

Human genetic data indicate that microglial dysfunction contributes to the pathology of Alzheimer's disease (AD), exemplified by the identification of coding variants in triggering receptor expressed on myeloid cells 2 (TREM2) and, more recently, in PLCG2, a phospholipase-encoding gene expressed in microglia. Although studies in mouse models have implicated specific Trem2-dependent microglial functions in AD, the underlying molecular mechanisms and translatability to human disease remain poorly defined. In this study, we used genetically engineered human induced pluripotent stem cell-derived microglia-like cells to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism. Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. Independent of TREM2, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses. Therefore, PLCγ2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and might be involved in the transition to a microglial state associated with neurodegenerative disease.

References

Feb 25, 2005·The Journal of Experimental Medicine·Kazuya TakahashiHarald Neumann
Oct 21, 2006·The Journal of Clinical Investigation·Dailing MaoRoberta Faccio
May 18, 2010·Biochimica Et Biophysica Acta·Paul Foley
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Nov 13, 2012·Annual Review of Physiology·Ganesh Kadamur, Elliott M Ross
Nov 16, 2012·The New England Journal of Medicine·Thorlakur JonssonKari Stefansson
Nov 16, 2012·The New England Journal of Medicine·Rita GuerreiroUNKNOWN Alzheimer Genetic Analysis Group
Aug 28, 2013·The Journal of Cell Biology·Sarah Huntwork-RodriguezJoseph W Lewcock
Jun 26, 2014·Nature Reviews. Immunology·Michael T HenekaEicke Latz
Sep 5, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ye ZhangJian Qian Wu
Jan 30, 2015·Nature Communications·Carlo CondelloJaime Grutzendler
Jan 30, 2015·Acta Neuropathologica·Claudia CantoniLaura Piccio
Apr 22, 2015·The Journal of Clinical Investigation·Pietro Luigi PolianiMarco Colonna
May 21, 2015·Nature Reviews. Neuroscience·Frank L HeppnerBurkhard Becher
Jan 19, 2016·Nature Biotechnology·John G DoenchDavid E Root
Apr 20, 2016·The Journal of Experimental Medicine·Yaming WangMarco Colonna
May 18, 2016·Nucleic Acids Research·Sasha BabickiDavid S Wishart
Jun 14, 2016·Nature Neuroscience·Shima SafaiyanMikael Simons
Nov 1, 2016·Nature Medicine·Julien MuffatRudolf Jaenisch
Oct 7, 2016·Advances in Biological Regulation·Yoe-Sik BaePann-Ghill Suh
Jan 20, 2017·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Taylor R JayGary E Landreth
Apr 21, 2017·Neuron·Jason D UlrichDavid M Holtzman
Apr 21, 2017·Neuron·Edsel M AbudMathew Blurton-Jones
Apr 23, 2017·Journal of Molecular Biology·Daniel L Kober, Tom J Brett
Jul 4, 2017·Nature Neuroscience·Thais F GalatroBart J L Eggen
Aug 13, 2017·Cell·Tyler K UllandMarco Colonna
Dec 3, 2017·The Journal of Cell Biology·David V HansenMorgan Sheng
Feb 9, 2018·Nature Communications·Marta OlahElizabeth M Bradshaw
Jun 3, 2018·Molecular Neurodegeneration·Paul J Cheng-HathawayGary E Landreth

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Citations

Sep 13, 2020·Molecular Neurodegeneration·Mari TakaloChristian Haass
Jul 11, 2020·International Journal of Molecular Sciences·Simon GutbierChristoph Patsch
Dec 10, 2020·Molecular Biology of the Cell·Vanessa F LangnessLawrence S B Goldstein
Dec 29, 2020·Frontiers in Immunology·Anne HedegaardSally A Cowley
Jan 5, 2021·Frontiers in Neuroscience·Yongji ZhouCaixiu Lin
Feb 2, 2021·Journal of Alzheimer's Disease : JAD·Fan ChenGuiyou Liu
Sep 23, 2020·Trends in Neurosciences·Louis-Philippe BernierBrian A MacVicar
Apr 13, 2021·Frontiers in Cellular Neuroscience·Thomas Ernest James Phillips, Emily Maguire
Sep 6, 2020·Progress in Retinal and Eye Research·Veer B GuptaVivek Gupta
Jun 19, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Zena K Chatila, Elizabeth M Bradshaw
Jun 23, 2021·The Journal of Biological Chemistry·Jacob T JacksonSeth L Masters
Jun 24, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Hyun-Sik YangRudolph E Tanzi
Jul 13, 2021·Frontiers in Aging Neuroscience·Femke M Feringa, Rik van der Kant
Jul 25, 2021·Nature Communications·Ganna LeonenkoValentina Escott-Price
Jul 25, 2021·Molecular Neurodegeneration·Christel ClaesMathew Blurton-Jones
Sep 3, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Wenhui Qu, Ling Li
Oct 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Hui JingBenjamin F Cravatt

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Datasets Mentioned

BETA
GSE144120

Methods Mentioned

BETA
gene knockout
fluorescence-activated cell sorting
co-immunoprecipitation
immunoprecipitation
PCR
chip
flow cytometry
AlphaLISA
Protein Assay

Software Mentioned

SCIEX
Prism
IDT
Skyline
DEBrowser
WebGestalt
MultiQuant
Image J
daily ( )
Fluidigm

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