Triggering receptor expressed on myeloid cells 2–Complement component 1q axis (TREM2–C1q axis)

The TREM2–C1q axis is a critical neuro-immune signaling pathway that regulates microglial activity and homeostasis within the central nervous system. Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is a transmembrane receptor primarily found on microglia that acts as a sensor for lipids, amyloid-beta, and other damage-associated molecular patterns [UniProt: Q9NZC2]. Recent evidence has identified Complement component 1q (C1q), the initiator of the classical complement pathway, as a high-affinity ligand for TREM2, suggesting that C1q bridges microglia to targets like damaged synapses or protein aggregates for phagocytic removal [PubMed: 36103858]. In neurodegenerative conditions such as Alzheimer's disease, dysregulation of this axis leads to impaired clearance of toxic proteins and aberrant synapse pruning, which accelerates cognitive decline [PubMed: 35143758]. Current drug development efforts focus on TREM2-activating antibodies, such as AL002 and VGL101, to bolster protective microglial functions, as well as C1q inhibitors like ANX005 to prevent complement-mediated neurodegeneration [Alector 2024, Annexon 2024]. This axis represents a major therapeutic frontier for modulating the innate immune response to treat chronic brain disorders.

Other names

TREM2-C1q interactionTREM2-complement pathwayC1q-TREM2 signalingMicroglial TREM2-C1q pathway

Therapeutic modulation involves agonizing TREM2 to enhance microglial phagocytic clearance of amyloid plaques and apoptotic debris, or inhibiting C1q to prevent the classical complement cascade from driving pathological synapse elimination [PubMed: 35143758, Alector 2024].