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Sustained Trem2 stabilization accelerates microglia heterogeneity and Aβ pathology in a mouse model of Alzheimer's
Rahul Dhandapani1, Marilisa Neri2, Mario Bernhard1
1Department of Neuroscience, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
Abstract:
TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer's disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. Here, we generate a transgenic mouse model of reduced Trem2 shedding (Trem2-Ile-Pro-Asp [IPD]) through amino-acid substitution of an ADAM-protease recognition site. We show that Trem2-IPD mice display increased Trem2 cell-surface-receptor load, survival, and function in myeloid cells. Using single-cell transcriptomic profiling of mouse cortex, we show that sustained Trem2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer's disease. Our data indicate that reduction of Trem2 proteolytic cleavage aggravates neuroinflammation during the course of Alzheimer's disease pathology, suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.
Insights
Reduced TREM2 shedding in Alzheimer's disease models worsens neuroinflammation. This suggests TREM2 cleavage is crucial for regulating microglial function during disease progression.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- TREM2 is a microglial receptor regulating brain inflammatory responses.
- TREM2 cleavage impacts microglial function and is linked to Alzheimer's disease (AD).
- The consequences of reduced TREM2 cleavage in AD remain unclear.
Purpose of the Study:
- To investigate the functional consequences of reduced TREM2 proteolytic cleavage.
- To generate and analyze a mouse model with impaired TREM2 shedding.
- To elucidate TREM2's role in microglial responses to amyloid-beta (Aβ) pathology.
Main Methods:
- Generated a transgenic mouse model (Trem2-IPD) with reduced TREM2 shedding via amino acid substitution.
- Analyzed Trem2-IPD mice for Trem2 cell-surface levels, myeloid cell survival, and function.
- Utilized single-cell transcriptomic profiling of mouse cortex to assess microglial responses in an AD model.
Main Results:
- Trem2-IPD mice exhibited increased Trem2 cell-surface receptor levels, enhanced myeloid cell survival, and improved function.
- Sustained TREM2 stabilization altered microglial maturation pathways.
- Reduced TREM2 shedding accelerated microglial responses to Aβ pathology in an AD mouse model.
Conclusions:
- Reduced TREM2 proteolytic cleavage aggravates neuroinflammation in the context of AD pathology.
- TREM2 shedding is a critical regulator of microglial activity in pathological conditions.
- Targeting TREM2 cleavage may offer therapeutic strategies for Alzheimer's disease.
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