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Updated: Feb 24, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Absence of CX3CR1 impairs the internalization of Tau by microglia
Marta Bolós1,2, María Llorens-Martín3,4,5, Juan Ramón Perea3,4
1Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, 28041, Madrid, Spain. mbolos@cbm.csic.es.
Background:
Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism.
Methods:
We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1-/- mice). The expression of CX3CR1, CX3CL1 and the microglial phagocytic phenotype were studied in brain tissue samples from AD patients.
Results:
Tau binding to CX3CR1 triggers the internalization of the former by microglia, whereas S396 Tau phosphorylation decreases the binding affinity of this protein to CX3CR1. Of note, the progressive increase in the levels of phosho-Tau occurred in parallel with an increase in CX3CR1. In addition, our studies suggest that the phagocytic capacity of microglia in brain tissue samples from AD patients is decreased. Furthermore, the CX3CR1/CX3CL1 axis may be impaired in late stages of the disease.
Conclusions:
Our data suggest that the CX3CR1/CX3CL1 axis plays a key role in the phagocytosis of Tau by microglia in vitro and in vivo and that it is affected as AD progresses. Taken together, our results reveal CX3CR1 as a novel target for the clearance of extracellular Tau.
Insights
The CX3CL1/CX3CR1 axis is crucial for microglia to clear toxic Tau in Alzheimer's disease (AD). This pathway is impaired in later AD stages, suggesting CX3CR1 as a therapeutic target for Tau removal.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Extracellular Tau protein accumulation contributes to Alzheimer's disease (AD) neurotoxicity and progression.
- The CX3CL1/CX3CR1 axis represents a critical signaling pathway for communication between neurons and microglia.
Purpose of the Study:
- To investigate the role of the CX3CL1/CX3CR1 axis in microglial Tau clearance.
- To determine if this axis is altered during Alzheimer's disease progression.
Main Methods:
- In vitro studies using primary microglia cultures and Cy5-Tau.
- In vivo experiments involving stereotaxic injection of Cy5-Tau into wild-type and CX3CR1 knockout mice.
- Analysis of CX3CR1, CX3CL1 expression, and microglial phagocytic phenotype in AD patient brain samples.
Main Results:
- Tau binding to CX3CR1 facilitates microglial internalization; however, Tau phosphorylation at S396 reduces this binding.
- Increased phospho-Tau levels correlate with elevated CX3CR1 expression, suggesting a complex regulatory mechanism.
- Microglial phagocytic capacity is diminished in AD patients, and the CX3CR1/CX3CL1 axis appears impaired in advanced disease stages.
Conclusions:
- The CX3CR1/CX3CL1 axis is vital for microglial Tau phagocytosis in both experimental models and human AD.
- CX3CR1 emerges as a potential therapeutic target for enhancing extracellular Tau clearance in Alzheimer's disease.
