Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

Area of Science:

• Neuroscience
• Genetics
• Immunology

Background:

• Alzheimer's disease (AD) is a leading cause of dementia.
• The TREM2 R47H variant significantly increases AD risk.
• TREM2-deficient microglia show impaired responses in AD models.

Purpose of the Study:

• To investigate the in vivo function of TREM2 variants in AD.
• To identify TREM2 ligands and the effect of the R47H variant in vivo.
• To understand TREM2's role in microglial activation around amyloid-β plaques.

Main Methods:

• Generated transgenic 5XFAD AD mouse models expressing human common variant (CV) or R47H TREM2.
• Assessed microgliosis and microglial activation in response to amyloid-β plaques.
• Analyzed soluble TREM2 localization in the brain.

Main Results:

• The CV TREM2 transgene restored amyloid-β-induced microgliosis and microglial activation.
• The R47H TREM2 transgene failed to restore these functions, indicating impaired in vivo activity.
• Soluble TREM2 was detected on neurons and plaques in CV-expressing mice, but not in R47H-expressing mice.

Conclusions:

• TREM2 R47H impairs TREM2 function in vivo, contrary to in vitro findings.
• TREM2 interacts with neurons and plaques during amyloid-β accumulation.
• The R47H variant disrupts this crucial interaction, contributing to AD pathogenesis.