| First Author | Schlepckow K | Year | 2020 |
| Journal | EMBO Mol Med | Volume | 12 |
| Issue | 4 | Pages | e11227 |
| PubMed ID | 32154671 | Mgi Jnum | J:351562 |
| Mgi Id | MGI:7702323 | Doi | 10.15252/emmm.201911227 |
| Citation | Schlepckow K, et al. (2020) Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med 12(4):e11227 |
| abstractText | Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., alpha-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for alpha-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid beta-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state. |
