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Updated: Nov 2, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Activated microglia mitigate Aβ-associated tau seeding and spreading
Maud Gratuze1,2,3, Yun Chen1,4,2,3, Samira Parhizkar1,2,3
1Department of Neurology, Washington University School of Medicine, St. Louis, MO.
Abstract:
In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.
Insights
Alzheimer's disease risk variants in TREM2 impact tau pathology. TREM2 activation of disease-associated microglia (DAM) is crucial for delaying tau spread in Alzheimer's disease models.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques and tau pathology.
- TREM2 gene variants are associated with AD risk, affecting microglial responses.
- The role of TREM2 in microglial function regarding tau pathology is not fully understood.
Purpose of the Study:
- To investigate the role of TREM2 and microglial function in the seeding and spreading of tau pathology in Alzheimer's disease models.
- To determine if microglial depletion and repopulation affect Aβ-driven tau propagation.
Main Methods:
- Utilized TREM2 knockout (TREM2KO) mouse models and microglial ablation/repopulation strategies.
- Assessed tau seeding and spreading in the presence and absence of microglia and TREM2.
- Analyzed disease-associated microglia (DAM) gene expression.
Main Results:
- Both TREM2 deficiency and microglial ablation significantly enhanced tau seeding and spreading around Aβ plaques.
- Microglial repopulation around plaques did not restore protective functions; instead, it showed reduced DAM gene expression and increased tau pathology.
- TREM2-dependent activation of the DAM phenotype is critical for mitigating Aβ-induced tau propagation.
Conclusions:
- TREM2-dependent microglial activation, specifically the DAM phenotype, is essential for delaying the pathological spread of tau aggregates in Alzheimer's disease.
- Loss of TREM2 function or microglial dysfunction exacerbates tau seeding and spreading, highlighting the protective role of activated microglia.
