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000151484 1001_ $$0P:(DE-2719)2812546$$aSchlepckow, Kai$$b0$$eFirst author
000151484 245__ $$aEnhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region
000151484 260__ $$aHeidelberg$$bEMBO Press$$c2020
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000151484 520__ $$aTriggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease‐associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full‐length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α‐secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α‐secretase‐mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho‐SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β‐peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9‐bound. Moreover, in a mouse model for Alzheimer's disease‐related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease‐associated state.
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000151484 650_2 $$2MeSH$$aAmyloid beta-Peptides
000151484 650_2 $$2MeSH$$aAnimals
000151484 650_2 $$2MeSH$$aAntibodies, Monoclonal: pharmacology
000151484 650_2 $$2MeSH$$aCell Line, Tumor
000151484 650_2 $$2MeSH$$aFemale
000151484 650_2 $$2MeSH$$aMacrophages
000151484 650_2 $$2MeSH$$aMembrane Glycoproteins: immunology
000151484 650_2 $$2MeSH$$aMice
000151484 650_2 $$2MeSH$$aMicroglia: pathology
000151484 650_2 $$2MeSH$$aMultiple Myeloma
000151484 650_2 $$2MeSH$$aRats
000151484 650_2 $$2MeSH$$aRats, Wistar
000151484 650_2 $$2MeSH$$aReceptors, Immunologic: immunology
000151484 7001_ $$aMonroe, Kathryn M$$b1
000151484 7001_ $$0P:(DE-HGF)0$$aKleinberger, Gernot$$b2
000151484 7001_ $$0P:(DE-2719)2812590$$aCantuti-Castelvetri, Ludovico$$b3
000151484 7001_ $$aParhizkar, Samira$$b4
000151484 7001_ $$aXia, Dan$$b5
000151484 7001_ $$0P:(DE-HGF)0$$aWillem, Michael$$b6
000151484 7001_ $$aWerner, Georg$$b7
000151484 7001_ $$aPettkus, Nadine$$b8
000151484 7001_ $$0P:(DE-2719)2810716$$aBrunner, Bettina$$b9
000151484 7001_ $$0P:(DE-2719)2810605$$aSülzen, Alice$$b10
000151484 7001_ $$0P:(DE-HGF)0$$aNuscher, Brigitte$$b11
000151484 7001_ $$aHampel, Heike$$b12
000151484 7001_ $$aXiang, Xianyuan$$b13
000151484 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b14
000151484 7001_ $$0P:(DE-2719)2442036$$aTahirovic, Sabina$$b15
000151484 7001_ $$aPark, Joshua I$$b16
000151484 7001_ $$aProrok, Rachel$$b17
000151484 7001_ $$aMahon, Cathal$$b18
000151484 7001_ $$aLiang, Chun‐Chi$$b19
000151484 7001_ $$aShi, Ju$$b20
000151484 7001_ $$aKim, Do Jin$$b21
000151484 7001_ $$aSabelström, Hanna$$b22
000151484 7001_ $$aHuang, Fen$$b23
000151484 7001_ $$aDi Paolo, Gilbert$$b24
000151484 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b25
000151484 7001_ $$00000-0003-3012-7881$$aLewcock, Joseph W$$b26
000151484 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b27$$eLast author
000151484 77318 $$2Crossref$$3journal-article$$a10.15252/emmm.201911227$$b : EMBO, 2020-03-10$$n4$$tEMBO Molecular Medicine$$v12$$x1757-4676$$y2020
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