Microglial fitness in moderation: Tuning TREM2 signaling through Ptpn6.

In this issue of Neuron, Etxeberria et al.1 report that Ptpn6 (SHP-1) restrains TREM2-driven microglial survival and DAM-like activation. Complete loss enhances amyloid containment and protects cortical neurites but triggers white matter degeneration, whereas partial reduction preserves benefit without harm-revealing that the threshold separating protective from detrimental microglial activation is regionally dissociable.