Mechanistic description
GluN2B signaling in cortical excitatory neurons releases fractalkine (CX3CL1) via activity-dependent TACE/ADAM17 shedding. CX3CL1 engages microglial CX3CR1 receptors, promoting TREM2-dependent phagocytosis of extracellular tau aggregates. Domain Expert recommends targeting downstream TREM2 rather than upstream GluN2B for superior druggability. Validated biomarker (CSF sTREM2) enables clinical development.
Evidence for (3)
CX3CL1-CX3CR1 signaling modulates tau pathology
TREM2 deficiency impairs tau phagocytosis
NMDAR activity regulates CX3CL1 shedding by TACE/ADAM17
Evidence against (2)
CX3CL1-CX3CR1 axis primarily mediates surveillance, not phagocytosis activation
TREM2 ligands include lipids and ApoE, not primarily CX3CR1 downstream