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000163471 0247_ $$2doi$$a10.15252/embj.2021109108
000163471 0247_ $$2pmid$$apmid:35019161
000163471 0247_ $$2pmc$$apmc:PMC8844989
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000163471 0247_ $$2ISSN$$a1460-2075
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000163471 037__ $$aDZNE-2022-00231
000163471 041__ $$aEnglish
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000163471 1001_ $$0P:(DE-2719)2812094$$aReifschneider, Anika$$b0$$udzne
000163471 245__ $$aLoss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency.
000163471 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2022
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000163471 520__ $$aHaploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
000163471 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000163471 650_7 $$2Other$$afrontotemporal lobar degeneration
000163471 650_7 $$2Other$$alysosomes
000163471 650_7 $$2Other$$amicroglia
000163471 650_7 $$2Other$$aneurodegeneration
000163471 650_7 $$2Other$$aprogranulin
000163471 650_7 $$2NLM Chemicals$$aAntibodies
000163471 650_7 $$2NLM Chemicals$$aGrn protein, mouse
000163471 650_7 $$2NLM Chemicals$$aMembrane Glycoproteins
000163471 650_7 $$2NLM Chemicals$$aProgranulins
000163471 650_7 $$2NLM Chemicals$$aReceptors, Immunologic
000163471 650_7 $$2NLM Chemicals$$aTREM2 protein, human
000163471 650_7 $$2NLM Chemicals$$aTrem2 protein, mouse
000163471 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aSYK protein, human
000163471 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aSyk Kinase
000163471 650_2 $$2MeSH$$aAnimals
000163471 650_2 $$2MeSH$$aAntibodies: immunology
000163471 650_2 $$2MeSH$$aAntibodies: pharmacology
000163471 650_2 $$2MeSH$$aBrain: diagnostic imaging
000163471 650_2 $$2MeSH$$aBrain: physiopathology
000163471 650_2 $$2MeSH$$aDisease Models, Animal
000163471 650_2 $$2MeSH$$aFemale
000163471 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000163471 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000163471 650_2 $$2MeSH$$aHumans
000163471 650_2 $$2MeSH$$aLysosomes: metabolism
000163471 650_2 $$2MeSH$$aLysosomes: pathology
000163471 650_2 $$2MeSH$$aMale
000163471 650_2 $$2MeSH$$aMembrane Glycoproteins: genetics
000163471 650_2 $$2MeSH$$aMembrane Glycoproteins: immunology
000163471 650_2 $$2MeSH$$aMembrane Glycoproteins: metabolism
000163471 650_2 $$2MeSH$$aMice, Inbred C57BL
000163471 650_2 $$2MeSH$$aMice, Knockout
000163471 650_2 $$2MeSH$$aMicroglia: drug effects
000163471 650_2 $$2MeSH$$aMicroglia: physiology
000163471 650_2 $$2MeSH$$aMonocytes: drug effects
000163471 650_2 $$2MeSH$$aMonocytes: metabolism
000163471 650_2 $$2MeSH$$aProgranulins: deficiency
000163471 650_2 $$2MeSH$$aReceptors, Immunologic: genetics
000163471 650_2 $$2MeSH$$aReceptors, Immunologic: immunology
000163471 650_2 $$2MeSH$$aReceptors, Immunologic: metabolism
000163471 650_2 $$2MeSH$$aSyk Kinase: metabolism
000163471 7001_ $$0P:(DE-2719)9000724$$aRobinson, Sophie$$b1$$udzne
000163471 7001_ $$avan Lengerich, Bettina$$b2
000163471 7001_ $$0P:(DE-2719)9001652$$aGnoerich, Johannes$$b3$$udzne
000163471 7001_ $$aLogan, Todd$$b4
000163471 7001_ $$00000-0003-3576-2702$$aHeindl, Steffanie$$b5
000163471 7001_ $$aVogt, Miriam A$$b6
000163471 7001_ $$0P:(DE-2719)9000882$$aWeidinger, Endy$$b7$$udzne
000163471 7001_ $$aRiedl, Lina$$b8
000163471 7001_ $$0P:(DE-2719)9001653$$aWind, Karin$$b9$$udzne
000163471 7001_ $$0P:(DE-2719)9001654$$aZatcepin, Artem$$b10$$udzne
000163471 7001_ $$0P:(DE-2719)2812778$$aPesämaa, Ida$$b11$$udzne
000163471 7001_ $$aHaberl, Sophie$$b12
000163471 7001_ $$0P:(DE-2719)9000236$$aNuscher, Brigitte$$b13$$udzne
000163471 7001_ $$0P:(DE-2719)9000907$$aKleinberger, Gernot$$b14$$udzne
000163471 7001_ $$00000-0003-0781-6400$$aKlimmt, Julien$$b15
000163471 7001_ $$aGötzl, Julia K$$b16
000163471 7001_ $$00000-0002-9069-2594$$aLiesz, Arthur$$b17
000163471 7001_ $$0P:(DE-2719)2811351$$aBürger, Katharina$$b18$$udzne
000163471 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b19$$udzne
000163471 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b20$$udzne
000163471 7001_ $$0P:(DE-2719)2811585$$aDiehl-Schmid, Janine$$b21$$udzne
000163471 7001_ $$aSuh, Jung$$b22
000163471 7001_ $$00000-0003-1032-1265$$aDi Paolo, Gilbert$$b23
000163471 7001_ $$00000-0003-3012-7881$$aLewcock, Joseph W$$b24
000163471 7001_ $$00000-0002-6901-1176$$aMonroe, Kathryn M$$b25
000163471 7001_ $$0P:(DE-2719)2010112$$aPaquet, Dominik$$b26$$udzne
000163471 7001_ $$0P:(DE-2719)9000368$$aCapell, Anja$$b27$$udzne
000163471 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b28$$eLast author$$udzne
000163471 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.2021109108$$gVol. 41, no. 4$$n4$$pe109108$$tThe EMBO journal$$v41$$x1460-2075$$y2022
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