TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is a key risk gene for Alzheimer's disease (AD).
• The precise mechanisms by which TREM2 influences AD pathogenesis remain incompletely understood.
• Microglial functions, including synaptic pruning, are implicated in neurodegeneration.

Purpose of the Study:

• To elucidate the functional role of TREM2 in the complement cascade and synaptic integrity in Alzheimer's disease.
• To identify the molecular interaction between TREM2 and complement C1q.
• To evaluate the therapeutic potential of targeting the TREM2-C1q interaction.

Main Methods:

• Immunohistochemistry on human AD brain samples to detect TREM2-C1q complexes.
• Biochemical assays to confirm TREM2 binding to C1q.
• Studies in AD mouse models (mutant human tau) with Trem2 haploinsufficiency.
• Administration of a TREM2-derived peptide in AD mouse models.

Main Results:

• TREM2 directly binds to C1q, inhibiting the classical complement cascade.
• TREM2-C1q complexes are present in human AD brains, correlating with C3 deposition and synaptic protein levels.
• Trem2 deficiency in mice enhances microglial synaptic engulfment and accelerates synaptic loss.
• A TREM2 peptide blocking C1q interaction rescues synaptic deficits in AD mouse models.

Conclusions:

• Microglial TREM2 plays a critical role in preventing excessive complement-mediated synaptic elimination in neurodegeneration.
• Targeting the TREM2-C1q interaction offers a potential therapeutic strategy for Alzheimer's disease.
• This study provides novel mechanistic insights into TREM2's protective function in AD.