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Updated: Mar 9, 2026
Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry
Published on: December 8, 2015
Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
William A McEwan1, Benjamin Falcon2, Marina Vaysburd2
1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; wmcewan@mrc-lmb.cam.ac.uk mg@mrc-lmb.cam.ac.uk lcj@mrc-lmb.cam.ac.uk.
Abstract:
Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.
Insights
Misfolded tau protein aggregates in Alzheimer's disease (AD) can be detected and neutralized by the body's own immune system. This cellular defense mechanism, involving antibodies and TRIM21, targets these harmful tau seeds similarly to viral infections.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) involves tau protein aggregation and spread within the brain.
- Misfolded tau spreads between cells, mimicking viral infection but evading immune detection.
- Host-derived misfolded proteins are not recognized as foreign by immune receptors.
Purpose of the Study:
- To investigate the cellular mechanisms for detecting and neutralizing misfolded tau aggregates.
- To explore the role of antibodies and cytosolic Fc receptors in combating tau seeding.
- To establish a rapid assay for measuring pathological tau formation.
Main Methods:
- Development of fluorescent, morphology-based seeding assays for in situ measurement of tau aggregates.
- Utilizing picomolar concentrations of tau seeds to trigger cellular responses.
- Tracking the interaction of anti-tau antibodies and tripartite motif protein 21 (TRIM21) with tau seeds.
Main Results:
- Anti-tau antibodies enter cells with tau seeds, recruiting TRIM21.
- TRIM21 neutralizes tau seeds intracellularly upon antibody binding.
- Neutralization involves the proteasome and AAA ATPase p97/VCP, similar to antiviral responses.
Conclusions:
- Intracellular antiviral immunity can be repurposed to target host-derived misfolded tau aggregates.
- Antibody-mediated recognition and TRIM21-dependent neutralization represent a novel defense against tau seeding.
- This mechanism offers a new perspective on cellular defense against neurodegenerative disease pathologies.
