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Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model
Published on: July 26, 2011
Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain
Noa Rachmian1,2, Sedi Medina2, Ulysse Cherqui1
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM). This senescent microglial protein signature was found in various mouse models that show cognitive decline, including aging, amyloidosis and tauopathy. TREM2-null mice had fewer microglia with a senescent signature. Treating 5×FAD mice with the senolytic BCL2 family inhibitor ABT-737 reduced senescent microglia, but not the DAM population, and this was accompanied by improved cognition and reduced brain inflammation. Our results suggest a dual and opposite involvement of TREM2 in microglial states, which must be considered when contemplating TREM2 as a therapeutic target in AD.
Insights
This study identifies senescent microglia expressing TREM2 in Alzheimer's disease models. Targeting these senescent cells with ABT-737 improved cognition and reduced brain inflammation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) and dementia are age-related, influenced by brain inflammation.
- Microglia, particularly those expressing the AD risk gene TREM2, are implicated but their role is unclear.
Purpose of the Study:
- To investigate the role of microglia, specifically TREM2-expressing cells, in Alzheimer's disease pathology.
- To identify distinct microglial states and their therapeutic potential.
Main Methods:
- Utilized high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis.
- Analyzed microglial protein signatures across various mouse models exhibiting cognitive decline.
- Investigated the effect of the senolytic ABT-737 on senescent microglia and cognitive function.
Main Results:
- Identified a senescent microglial population expressing high TREM2, distinct from disease-associated microglia (DAM).
- This senescent signature was present in aging, amyloidosis, and tauopathy mouse models.
- TREM2-null mice showed reduced senescent microglia.
- ABT-737 treatment decreased senescent microglia, improved cognition, and reduced neuroinflammation in 5×FAD mice.
Conclusions:
- TREM2 exhibits dual and opposing roles in different microglial states within AD.
- Senescent microglia represent a potential therapeutic target for Alzheimer's disease.
- Targeting senescent microglia may offer a novel strategy for AD treatment, distinct from targeting DAM.
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