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TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance

EMBO Molecular Medicine. 2016 July 8. pii: e201606370. DOI: 10.15252/emmm.201606370. [Epub ahead of print]

Authors/Editors: Xiang X, Werner G, Bohrmann B, Liesz A, Mazaheri F, Capell A, Feederle R, Knuesel I, Kleinberger G, Haass C.
Publication Date: 2016

2016_07_xiang

Abstract

Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer’s disease (AD). Antibodies against amyloid b-peptide (Ab) 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 Ab 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 Ab. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti-Ab antibodies stimulate Ab 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 antibodybound Ab 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 compensatednby elevating the concentration of therapeutic antibodies.

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