TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a microglial gene involved in the pathogenesis of Alzheimer’s disease (AD). Heterozygous mutations in the microglial gene have been identified to impair antibodies-induced Aβ clearance via the microglia, an immunotherapeutic approach for treatment of AD. This paper investigated whether antibody-mediated clearance of Aβ may be influenced by TREM2 deficiency. By using N9 microglial cells (CRISPR/Cas-9 modified), bone-marrow derived macrophages (BMDM), and primary microglial cells from mice (both wt and TREM2 knockout), the antibody-mediated phagocytosis of pre-formed Aβ fibrils or engulfment of antibody covered amyloid plaques from brain cryosections obtained from an AD mouse model were studied. Results revealed that loss of TREM2 significantly reduced uptake of pre-aggregated HiLyteTM Fluor 488-labeled Aβ42 (fAβ42) (AnaSpec)(figure). In addition, fAβ42 uptake was greatly stimulated upon antibody binding to both wt and Trem2 knockout mice BMDM, although there was reduction in the overall uptake capacity in BMDM Trem2 knockout. When cryosections of APP/PS1 (amyloid precursor protein/presenilin 1) mice were incubated with BMDM derived from wt or Trem2 knockout mice, a significant TREM2-dependent reduction in amyloid plaque clearance was observed. These findings, in concurrence with antibody titration assays showing reduced Aβ clearance by TREM2 knock out mice, suggest that phagocytic defects caused by loss of TREM2 function would require a higher immunotherapeutic antibody dose in order to clear the amyloid plaque efficiently. Monitoring microglial and TREM2 functions in patients at risk for AD may be necessary for suitable immunotherapeutic strategies relevant to efficient Aβ uptake and amyloid clearance. Citation: Xiang, X., Werner, G., Bohrmann, B., Liesz, A., Mazaheri, F., Capell, A., Feederle, R., Knuesel, I., Kleinberger, G., Haass, C. (2016). TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med. doi: 10.15252/emmm.201606370