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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift EMBO Molecular Medicine
Quellenangaben Band: 8, Heft: 9, Seiten: 992-1004 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Chichester
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
CF Monoclonal Antibodies (CF-MAB)