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

Jonathan X. Meng, Yu Zhang, Dominik Saman, Arshad M. Haider, Suman De, Jason C. Sang, Karen Brown, Kun Jiang, Jane Humphrey, Linda Julian, Eric Hidari, Steven F. Lee, Gabriel Balmus, R. Andres Floto, Clare E. Bryant, Justin L. P. Benesch, Yu Ye and David Klenerman ()
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Jonathan X. Meng: University of Cambridge
Yu Zhang: University of Cambridge
Dominik Saman: University of Oxford
Arshad M. Haider: UK Dementia Research Institute at Cambridge
Suman De: University of Cambridge
Jason C. Sang: University of Cambridge
Karen Brown: University of Cambridge
Kun Jiang: University of Cambridge
Jane Humphrey: University of Cambridge
Linda Julian: University of Cambridge
Eric Hidari: UK Dementia Research Institute at Cambridge
Steven F. Lee: University of Cambridge
Gabriel Balmus: UK Dementia Research Institute at Cambridge
R. Andres Floto: University of Cambridge
Clare E. Bryant: University of Cambridge
Justin L. P. Benesch: University of Oxford
Yu Ye: University of Cambridge
David Klenerman: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30461-x

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