1 research outputs found
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a diseaseāassociated microglial state. To enhance TREM2 activity, we sought to selectively increase the fullālength protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., Ī±āsecretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for Ī±āsecretaseāmediated 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 phosphoāSYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid Ī²āpeptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all oluble TREM2 was 4D9ābound. Moreover, in a mouse model for Alzheimer's diseaseārelated pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a diseaseāassociated state