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Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia
Na Zhao1, Wenhui Qiao1, Fuyao Li1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
Abstract:
TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.
Insights
Enhancing TREM2 signaling may treat Alzheimer's disease (AD). TREM2-WT is beneficial early in AD, while the R47H variant worsens amyloid pathology later, indicating a critical therapeutic window.
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.
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