TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function

Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to beta-amyloid (A beta) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce A beta binding. TREM2 deficiency impairs A beta degradation in primary microglial culture and mouse brain. A beta-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by A beta, regulating downstream phosphorylation of SYK and GSK3 beta. Our data demonstrate TREM2 as a microglial A beta receptor transducing physiological and AD-related pathological effects associated with A beta.