Our most advanced therapeutic programs are aimed at developing activators of TREM2, a transmembrane receptor expressed specifically on microglia in the brain
TREM2 is required for both microglial homeostatic maintenance functions and responses to inflammatory CNS damage in various disease states. Functional TREM2 acts as a receptor for damage ligands in the brain.
When there is a loss of function of TREM2, the microglia’s natural response to damage is compromised. Without TREM2 sensing and responding to damage ligands, microglia aren’t converted to a neuroprotective state, leading to an accumulation of debris and ultimately neurodegeneration.
TREM2 signals flow through a coordinated signaling complex that includes intracellular proteins DAP12, SYK, which binds to the phosphorylated ITAM domain of DAP12, and SRC. The signals originating from TREM2 activation promote cell migration to sites of brain injury due to neuronal death, myelin turnover, or aggregated protein accumulation, as well as promoting microglial survival, phagocytosis, and proliferation. Taken together, these microglia-mediated functional responses to injury and inflammation act as an essential deterrent to catastrophic neural degeneration that is a hallmark of adult onset neurodegenerative diseases.
TREM2: Required for Microglial Function
Microglial Dysfunction with Defective TREM2
Vigil's TREM2 Agonist to Restore Microglial Function
Compelling evidence for the critical role that TREM2 plays to prevent neurodegeneration comes from studies linking mutations causing TREM2 deficiency with neurodegenerative diseases. TREM2 gene mutations, also referred to as variants, represent one of the biggest risk factors for Alzheimer’s disease. Animal model data indicate that therapeutically activating TREM2 can ameliorate neuropathology associated with TREM2 deficiency. This is a foundation of our rationale for therapeutically activating TREM2 signaling to treat neurodegenerative diseases.