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EMBO Mol Med. 2016 Sep 1;8(9):992-1004. doi: 10.15252/emmm.201606370. Print 2016 Sep.

TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.

Author information

1
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, Germany.
2
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
3
Roche Pharmaceutical Research and Early Development NORD Discovery & Translational Area, Roche Innovation Center Basel, Basel, Switzerland.
4
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
5
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
6
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.
7
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
8
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.

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.

KEYWORDS:

Alzheimer's disease; TREM2; immunotherapy; neurodegeneration; phagocytosis

PMID:
27402340
PMCID:
PMC5009806
DOI:
10.15252/emmm.201606370
[Indexed for MEDLINE]
Free PMC Article

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