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Updated: Jun 13, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Bing Zhu1, Yan Liu1, Spring Hwang1
1Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Background:
Alzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer's disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive.
Methods:
Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes.
Results:
Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia.
Conclusion:
Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.
Insights
Loss of TREM2 function in microglia enhances tau pathology spread and seeding via exosomes, contributing to Alzheimer's disease progression and memory deficits. This highlights TREM2's role in suppressing exosomal tau pathogenicity.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) involves progressive Aβ and tau pathology.
- Microglial TREM2 variants increase sporadic AD risk.
- TREM2's role in modulating tau pathology remains unclear.
Purpose of the Study:
- Investigate TREM2's impact on tau spreading and pathogenicity.
- Characterize TREM2-dependent microglial exosome function in tauopathy.
Main Methods:
- Utilized wildtype and Trem2 knockout mice with AAV-P301L tau injection.
- Employed microfluidic assays for in vitro neuronal-microglial co-culture.
- Analyzed tau uptake, trafficking, exosomal secretion, and pathogenicity.
Main Results:
- TREM2 deficiency enhanced tau spreading from MEC to hippocampus, impairing memory.
- Microglial TREM2 deletion increased intraneuronal tau dispersion and exosomal tau levels.
- Exosomes from TREM2-deficient microglia exhibited heightened tau seeding capacity.
Conclusions:
- TREM2 normally suppresses exosomal tau pathogenicity.
- TREM2 deletion promotes tau trafficking, distribution, and seeding via microglial exosomes.
