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The TREM2 R47H variant exacerbates Alzheimer's disease pathology by impairing microglial response to amyloid plaques. Human TREM2 R47H knock-in mice show increased plaque load and failed homeostatic gene regulation.

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Area of Science:

  • Neuroscience
  • Genetics
  • Immunology

Background:

  • The TREM2 R47H variant is a significant genetic risk factor for late-onset Alzheimer's disease (LOAD).
  • This variant impairs microglial reactivity to amyloid-beta (Aβ) plaques, potentially accelerating Alzheimer's disease (AD) progression.

Purpose of the Study:

  • To develop and characterize novel mouse models for LOAD using human TREM2 (hTREM2) and hTREM2-R47H knock-in strategies.
  • To investigate the impact of the microglial TREM2-R47H variant on AD pathology development in vivo.

Main Methods:

  • Generated hTREM2 and hTREM2-R47H knock-in mouse lines, crossed with 5xFAD mice.
  • Analyzed amyloid pathology and glial responses using immunohistochemistry (IHC) at 4 and 12 months.
  • Performed spatial transcriptomic analysis using CosMx to assess glial cell type-specific gene expression.

Main Results:

  • 5xFAD mice with hTREM2-R47H exhibited increased amyloid plaque load and spread in the cortex and subiculum at 4 months.
  • Microglia in hTREM2-R47H mice showed impaired response to plaques and failed to downregulate homeostatic genes (e.g., P2ry12, Tmem119).
  • Human TREM2 (hTREM2) alone showed reduced functionality compared to murine Trem2 (mTrem2) in the mouse system.

Conclusions:

  • Human TREM2 R47H microglia exhibit a distinct lack of homeostatic gene downregulation in response to amyloid-beta.
  • The R47H variant's detrimental effect on microglial function appears stronger in the humanized TREM2 context.
  • Humanization of disease-relevant genes like TREM2 provides valuable insights into Alzheimer's disease mechanisms.