TREM2 and APOE are dispensable for microglial clearance of dying neurons revealed by in vivo imaging.

TREM2 and APOE are major Alzheimer's disease (AD) risk genes that may influence microglial pathophysiology by affecting their ability to phagocytose cellular debris and protein aggregates. Here, we investigated the impact of TREM2 and APOE on the removal of dying neurons in the live brain by combining a targeted photochemical method for programmed cell death with high-resolution two-photon imaging in adult mice. We show that deletion of either Trem2 or Apoe does not affect the dynamics of microglia engagement with dying neurons or their efficiency in phagocytosing corpses. Notably, microglia encapsulating amyloid deposits phagocytosed nearby dying cells without disengaging from plaques or moving their cell bodies; however, in the absence of TREM2, microglial cell bodies readily migrated toward dying cells, subsequently disengaging from plaques. These findings indicate TREM2 and APOE variants likely confer AD risk through mechanisms independent of impaired neuronal corpse phagocytosis.