title: TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.
abstract: Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β-peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor-mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody-mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti-Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose-dependent manner in the presence or absence of TREM2. However, TREM2-deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody-bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Xianyuan
authors.initials: X
authors.lastname: Xiang
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Werner
authors.affiliation: Roche Pharmaceutical Research and Early Development NORD Discovery & Translational Area, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
authors.forename: Fargol
authors.initials: F
authors.lastname: Mazaheri
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Capell
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany Helmholtz Center Munich, German Research Center for Environmental Health, Institute for Diabetes and Obesity Core Facility Monoclonal Antibody Development, Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Feederle
authors.affiliation: Roche Pharmaceutical Research and Early Development NORD Discovery & Translational Area, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Irene
authors.initials: I
authors.lastname: Knuesel
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany christian.haass@mail03.med.uni-muenchen.de.
authors.forename: Christian
authors.identifier: 0000-0003-2629-0723
authors.initials: C
authors.lastname: Haass
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D008562:Membrane Glycoproteins / Q000172:deficiency*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000276:immunology* / Q000502:physiology; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000172:deficiency*
chemical_list: D000682:Amyloid; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse
keywords: Alzheimer's disease; TREM2; immunotherapy; neurodegeneration; phagocytosis