Cited by 84Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsPrion Diseases and Protein Misfolding

Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses

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Meng, Jonathan X., Zhang, Yu, Saman, Dominik, Haider, Arshad M., De, Suman, Sang, Jason C., Brown, Karen, Jiang, Kun +10 more·2022·Nature Communications

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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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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
Venue
Nature Communications
Published
2022-05-16
Volume
13
Issue
1
Pages
2692-2692
ISSN
2041-1723 (ISSN-L)
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
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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