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TREM2 Is a Receptor for ?-Amyloid that Mediates Microglial Function.

ABSTRACT: 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 ?-amyloid (A?) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce A? binding. TREM2 deficiency impairs A? degradation in primary microglial culture and mouse brain. A?-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?, regulating downstream phosphorylation of SYK and GSK3?. Our data demonstrate TREM2 as a microglial A? receptor transducing physiological and AD-related pathological effects associated with A?.

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC5889092 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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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 β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K<sup>+<  ...[more]

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