Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.
Haider, Arshad M
Sang, Jason C
Springer Science and Business Media LLC
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Meng, J. X., Zhang, Y., Saman, D., Haider, A. M., De, S., Sang, J. C., Brown, K., et al. (2022). Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.. Nat Commun, 13 (1) https://doi.org/10.1038/s41467-022-30461-x
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.
Humans, Tauopathies, Heparin, tau Proteins, Protein Isoforms, Phosphorylation, Toll-Like Receptor 4, Protein Aggregation, Pathological, Glycogen Synthase Kinase 3 beta
J.X.M. is supported by Dr. Herchel Smith Fellowship from Williams College .Y.Z. is supported by the Wellcome Trust Grant (107032AIA, R.A.F). and the Cambridge Cancer Center Pump Priming Grant and Royal Society University Research Fellowship to S.F.L. D.S. is supported by Clarendon Scholarship from Oxford University Press. A.M.H. is funded by Open Targets. G.B. Y.Y. are supported by the UK Dementia Research Institute that receives contributions from UK DRI Ltd, the UK MRC, the Alzheimer’s Society, and Alzheimer’s Research UK. C.E.B. is supported by a Wellcome Trust Investigator award (108045/Z/15/Z, C.E.B.). This work is supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK and by the Royal Society (RP150066, DK).
European Research Council (669237)
Royal Society (RSRP\R\210003)
Wellcome Trust (108045/Z/15/Z)
Wellcome Trust (107032/B/15/Z)
External DOI: https://doi.org/10.1038/s41467-022-30461-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338176
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/