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Xiang, X.* ; Werner, G.* ; Bohrmann, B.* ; Liesz, A.* ; Mazaheri, F.* ; Capell, A.* ; Feederle, R. ; Knuesel, I.* ; Kleinberger, G.* ; Haass, C.*

TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.

EMBO Mol. Med. 8, 992-1004 (2016)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Alzheimer's Disease ; Trem2 ; Immunotherapy ; Neurodegeneration ; Phagocytosis; Alzheimers-disease; Microglial Response; In-vivo; Beta; Bace1; Phagocytosis; Pathology; Macrophages; System; Model
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Journal EMBO Molecular Medicine
Quellenangaben Volume: 8, Issue: 9, Pages: 992-1004 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Chichester
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
CF Monoclonal Antibodies (CF-MAB)