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

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer's disease (AD) risk.
• The precise neurobiological roles of TREM2 and its ligands in AD pathophysiology are not fully understood.

Purpose of the Study:

• To investigate the direct binding of TREM2 to amyloid-beta (Aβ) oligomers.
• To elucidate the functional consequences of TREM2-Aβ interaction on microglial responses and downstream signaling pathways relevant to Alzheimer's disease.

Main Methods:

• Biochemical assays to assess TREM2 binding affinity to Aβ oligomers.
• Primary microglial cultures and mouse brain models to evaluate Aβ degradation and TREM2-dependent microglial functions.
• Analysis of TREM2-DAP12 complex formation and downstream signaling (SYK, GSK3β phosphorylation).

Main Results:

• TREM2 directly binds to Aβ oligomers with nanomolar affinity; AD-associated mutations significantly reduce this binding.
• TREM2 deficiency impairs Aβ degradation in both cellular and in vivo models.
• Aβ-induced microglial responses, including depolarization, cytokine release, migration, proliferation, apoptosis, and morphological changes, are TREM2-dependent.
• Aβ enhances the interaction between TREM2 and its signaling adaptor DAP12, modulating SYK and GSK3β phosphorylation.

Conclusions:

• TREM2 functions as a direct microglial receptor for Aβ oligomers.
• TREM2 signaling is critical for mediating microglial responses to Aβ, influencing both physiological functions and pathological processes in Alzheimer's disease.
• These findings identify TREM2 as a key player in AD pathogenesis, linking genetic risk to molecular mechanisms of disease progression.