Journal Article

TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance

Mazaheri, Fargol, Feederle, Regina, Werner, Georg, Capell, Anja, Xiang, Xianyuan, Haass, Christian, Bohrmann, Bernd, Kleinberger, Gernot, Knuesel, Irene, Liesz, Arthur

2016

Overview

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. Synopsis TREM2‐deficient phagocytic cells do not uptake antibody‐bound Aβ well, resulting in reduced clearance of amyloid plaques. This, however, can be compensated by elevated concentrations of immunotherapeutic antibodies, highlighting that monitoring microglia function in Alzheimer's disease is important. TREM2 deficiency reduces uptake of antibody‐bound Aβ by phagocytic cells. TREM2 deficiency lowers the efficacy of immunotherapeutic amyloid plaque clearance. Elevated anti‐Aβ antibody concentrations improve the phagocytic capacity of Trem2‐deficient cells. Graphical Abstract TREM2‐deficient phagocytic cells do not uptake antibody‐bound Aβ well, resulting in reduced clearance of amyloid plaques. This, however, can be compensated by elevated concentrations of immunotherapeutic antibodies, highlighting that monitoring microglia function in Alzheimer's disease is important.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Inc,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Alzheimer's disease / Amyloid - metabolism / Animals / Antibodies / Bone marrow / Cell lines / Cells, Cultured / Clinical trials / CRISPR / Drug therapy / EMBO19 / EMBO27 / EMBO28 / Fc receptors / Immunoglobulins / Immunotherapy / Macrophages / Membrane Glycoproteins - deficiency / Memory / Mice, Inbred C57BL / Mice, Knockout / Microglia / Mutation / Myeloid cells / neurodegeneration / Neurodegenerative diseases / Neuroglia - immunology / Neuroglia - physiology / Pathology / Peptides / Phagocytosis / Receptors, Immunologic - deficiency / Research Article / Senile plaques / Titration / TREM2 / Viral antibodies / β-Amyloid