Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• TREM2 (triggering receptor expressed myeloid cells 2) is a microglial receptor crucial for brain immune responses.
• TREM2 dysfunction is linked to increased Alzheimer's disease (AD) risk.
• Targeting TREM2 signaling is a potential therapeutic strategy for AD.

Purpose of the Study:

• To investigate the therapeutic window for TREM2 modulation in Alzheimer's disease.
• To compare the effects of wild-type TREM2 (TREM2-WT) and the R47H risk variant (TREM2-R47H) on AD pathogenesis.

Main Methods:

• Utilized microglia-specific inducible mouse models overexpressing human TREM2-WT or TREM2-R47H.
• Analyzed amyloid deposition and neuritic dystrophy.
• Performed single-cell RNA sequencing to assess microglial states and pathways.

Main Results:

• TREM2-WT expression reduced amyloid deposition and neuritic dystrophy during the early amyloid seeding stage.
• TREM2-R47H expression exacerbated amyloid burden during the middle amyloid rapid growth stage.
• TREM2-WT suppressed the disease-associated microglia (DAM) signature early on; TREM2-R47H upregulated antigen presentation pathways mid-stage.

Conclusions:

• TREM2's role in AD pathogenesis is dynamic and stage-dependent.
• Enhancing TREM2 function early in AD development shows therapeutic potential.
• The TREM2 R47H variant may have detrimental effects during specific disease stages.