Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Coding variants in TREM2 (triggering receptor expressed on myeloid cells 2) are linked to late-onset Alzheimer's disease (AD).
• Microglia play a crucial role in brain immunity and AD pathogenesis.
• Apolipoprotein E (ApoE) is implicated in AD, with its deposition in plaques being a key feature.

Purpose of the Study:

• To investigate the role of TREM2 in amyloid plaque seeding and early Alzheimer's disease pathogenesis.
• To elucidate the relationship between TREM2, microglial function, and ApoE deposition in amyloid plaques.
• To understand the impact of TREM2 variants on amyloidogenesis over time.

Main Methods:

• Utilized mouse models with Trem2 loss-of-function mutations.
• Employed amyloid plaque seeding assays.
• Conducted longitudinal amyloid positron emission tomography (PET) imaging.
• Performed proteomic analyses and microglia depletion experiments.

Main Results:

• Absence of functional Trem2 led to increased amyloid plaque seeding.
• Microglial clustering around new plaques and plaque-associated ApoE were reduced in Trem2 mutants.
• Reduced ApoE deposition was also observed in human AD brains with TREM2 variants.
• Microglia were identified as a source of plaque-associated ApoE.
• Trem2 loss-of-function mutants showed accelerated early amyloidogenesis, with slower progression later in life.

Conclusions:

• Functional TREM2 is critical for efficient phagocytic clearance of amyloid seeds.
• Loss of TREM2 function accelerates early amyloidogenesis in Alzheimer's disease.
• Impaired microglial function, rather than reduced ApoE, appears to drive accelerated amyloidogenesis in the absence of TREM2.