Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
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Abstract
Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.
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Hyperphosphorylated tau can disrupt membrane bilayers and activate human macrophages through TLR4.
“Meng et al. further demonstrated that the hyperphosphorylated tau can disrupt membrane bilayers and activate human macrophages through TLR4.46”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [46]
Aggregates formed by hyperphosphorylated tau can induce human macrophage activation in a TLR4-dependent manner.
“Just several months ago, Meng et al. reported that aggregates formed by hyperphosphorylated tau can induce human macrophage activation in a TLR4-dependent manner.46”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [46]
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BackgroundResultInfluentialMicroglial activation states and their implications for Alzheimer's Disease
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Self-citationAstrocyte-driven vasoconstriction impairs glymphatic clearance in a human tauopathy-on-chip model
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Self-citationSeed structure and phosphorylation in the fuzzy coat impact tau seeding competency
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Self-citationMolecular functions of ANKLE2 and its implications in human disease
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Chemical Strategies to Modulate Amyloidogenesis Associated with Neurodegenerative Diseases
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Single-Oligomer Characterization of Tau Phosphorylation and Mechanical State
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Type-1 interferons associated with microglial-mediated neuroinflammation in Alzheimer’s disease
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Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models
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In situ seeding assay: A novel technique for direct tissue localization of bioactive tau
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Listerin Alleviates Alzheimer's Disease through IRE1‐mediated Decay of TLR4 mRNA
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The biological diagnosis of Alzheimer’s disease using blood-based biomarkers: A Canadian prospective
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Small tau aggregates exhibit disease-specific molecular profiles across tauopathiesPreprint
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Tau Folding and Assembly Triggered by Electroreduction of Its Protonated Amino Acids
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Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration
Risby-Jones, G., Lee, J. D., & Fung, J. N. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2026.07.002 · Cited by 1 · see citing works
Brain Aging and Cellular Senescence Trigger Neuroimmunological Dysregulation and Neurodegeneration
Vega-García, A., Apolinar, L. M., Feria-Romero, I. A., Campos‐Bedolla, P., Alberto, G.-G. C., Luna‐Munguía, H., Sofía, R.-H., & Orozco-Suárez, S. A. (2026) · Brain Sciences · doi:10.3390/brainsci16101019 · Cited by 1 · see citing works
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Self-citationDietary Interventions in Neurodegenerative Diseases
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The role of specific phosphorylation patterns in the oligomerization of Tau-R4Preprint
Bressler, S., Grunhaus, D., Aviram, A., Rüdiger, S., Hurevich, M., & Friedler, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.14.628478
Analytical considerations and clinical utility of plasma phosphorylated Tau217
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The biological diagnosis of Alzheimer’s disease using blood-based biomarkers: a Canadian prospective
Kumar, P., Mousavi, A., & Frykman, H. (2025) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2025.111015
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TLR4 Targeting Probe Design Using in silico Structural Insights
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Phosphorylated peptide Tau-pT181 induced tau aggregation and cognitive dysfunction
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The role of the α7 nicotinic acetylcholine receptor in a model of amyloid pathology
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Site-specific phosphorylation of Ser352 drives aggregation of Tau R4 under acidosis conditionsPreprint
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Visceral adipose tissue differentially affects tau and Aβ pathology in 3xTg-AD mice
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Targeted dephosphorylation of Tau at the endogenous level promotes its association with microtubulesPreprint
Sathe, G. J., Berterame, F., Cartwright, T. N., Spallek, R., Zhao, J., Bagale, A. R., Gourlay, R., Wood, N. T., Macartney, T., & Sapkota, G. P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.07.749800
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- Authors
- Meng, J. X., Zhang, Y., Saman, D., Haider, A. M., De, S., Sang, J. C., Brown, K., Jiang, K., Humphrey, J., Julian, L., Hidari, E., Lee, S. F., Balmus, G., Floto, R. A., Bryant, C. E., Benesch, J. L. P., Ye, Y., & Klenerman, D.
- Affiliations
- University of Cambridge (GB)
- MRC Laboratory of Molecular Biology (GB)
- UK Dementia Research Institute (GB)
- University of Oxford (GB)
- Corresponding author
- Klenerman, David
- ORCID
- Venue
- Nature Communications
- Published
- 2022-05-16
- Volume
- 13
- Issue
- 1
- Pages
- 2692-2692
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9110413
- OpenAlex
- W4280496858
- Cited by
- 84
- References
- 89
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 22 · 2023: 12 · 2022: 4
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- Royal Society (RP150066)
- RCUK | Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- tau hyperphosphorylation, tauopathy, protein kinase A, glycogen synthase kinase-3β, MAPKAPK4, phosphorylation sites, membrane damage, TLR4, macrophages, neuroinflammation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Heparin, Humans, Phosphorylation, tau Proteins, Protein Isoforms, Tauopathies, Toll-Like Receptor 4, Protein Aggregation, Pathological
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