Therapeutic targeting of TREM2: A novel approach for treatment of AD?

Abstract Background Genome‐wide association studies have revealed risk genes for developing late‐onset AD many of which are exclusively expressed by microglia in the brain. One of these microglial genes is TREM2. Studies employing mouse models of amyloid pathology have shown that TREM2 function is essential for microglia to mount a proper response to amyloid pathology. The fact that microglia exert protective effects via TREM2 at least at the early stages of amyloid deposition suggests that boosting TREM2 function pharmacologically during the early stages of AD may be a promising novel therapeutic approach. Method We have developed and evaluated the protective potential of agonistic anti‐TREM2 antibodies boosting TREM2 function in preclininal models of amyloid pathology and related disorders employing immunoblotting, ELISA, immunohistochemistry, scRNA‐seq, lipidomics, and TSPO‐ as well as FDG‐PET imaging. Result Our agonistic anti‐TREM2 antibody 4D9 binds 12 amino acids N‐terminal of the ectodomain cleavage site, inhibits proteolytic TREM2 cleavage, and potently activates downstream pSYK signaling. Boosting TREM2 signaling by 4D9 leads to improved survival of macrophages, enhanced phagocytic activity of primary microglia, lower amyloid burden in an AD mouse model as well as accelerated recovery in mouse models of demyelination. In more recent work we focused on the development of a version of 4D9 with an engineered Fc part, which allows very efficient transcytosis of the antibody across the blood brain barrier (ATV:4D9; ATV: antibody transport vehicle). We demonstrate in an AD mouse model by TSPO and FDG PET imaging that a human specific version of the antibody enhances microglial activation and brain glucose metabolism, respectively. Conclusion Several independent studies including our own efforts have convincingly shown amelioration of amyloid pathology in preclinical models of AD upon administration of agonistic anti‐TREM2 antibodies. Together with findings demonstrating reduced cognitive decline in patients with higher levels of CSF soluble TREM2, which serves as a surrogate marker for TREM2‐dependent microglial activity, this suggests that TREM2‐boosting therapies should be actively explored in the clinical setting. In addition, our work indicates that TSPO‐ and FDG‐PET imaging may be used to assess target engagement.