TREM2 Is a Receptor for β-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 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 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 Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.

Alterations in brain TREM2 and Amyloid‐β levels are associated with neurocognitive impairment in HIV‐infected persons on antiretroviral therapy

“…Moreover, decreased membrane‐bound TREM2 is associated with reduced uptake of Aβ (Zhao et al . ). To determine levels of Aβ 1‐42 and1‐40 in the brains of our cohort, we analyzed brain lysates using the Aβ triplex Mesoscale Discovery kit.…”

“…; Zhao et al . ). Microglia survey the environment for cues on the disease state, interacting with extracellular milieu, other glial cells, and neurons (Tang and Le ).…”

“…; Tang and Le ; Zhao et al . ). Although, the M1/M2 distinction is recognized as overly simplified, macrophages and microglia expressing TREM2 have a more anti‐inflammatory phenotype (Painter et al .…”

The role of gut microbiota in pathogenesis of Alzheimer's disease

“…Finally, upon evaluating the levels of CD68 and Lgals3 protein markers showing microglial phagocytosis, they found a significant increase in microglial‐associated Aβ phagocytosis in the cortex of 5xFAD/TREM2 mice, which is in agreement with the other in vitro study (Zhao et al . ) indicating the knockdown of TREM2 expression decreased Aβ clearance. In addition, Li et al .…”

“…) and in vitro (Zhao et al . ) studies performed simultaneously in two different laboratories. In these studies, it was shown that microbial amyloids act as a TREM2 ligand and that increasing level of TREM2 expression in BAC transgenic mice expressing human TREM2 (BAC‐TREM2) can significantly increase the degradations of Aβ 40 and Aβ 42 loads, which result in an improvement in AD phenotype; furthermore, upon examining the structures of Aβ plaques, they observed that Aβ plaques were mainly in inert form rather than the filamentous structure in 5xFAD/TREM2 mice.…”