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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.

Jonathan X Meng1,2, Yu Zhang1,3,4, Dominik Saman5

  • 1Department of Chemistry, University of Cambridge, Cambridge, UK.

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|May 16, 2022
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Summary
This summary is machine-generated.

Hyperphosphorylated tau protein (tau) can spontaneously form toxic aggregates. These aggregates damage cell membranes and trigger inflammatory responses, suggesting a mechanism for neuroinflammation in tauopathies.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Soluble tau aggregates are implicated in tauopathies but are difficult to study.
  • Understanding tau aggregate formation is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the spontaneous polymerization of hyperphosphorylated tau into aggregates.
  • To characterize the morphology and functional consequences of these self-assembled tau aggregates.

Main Methods:

  • Recombinant wild-type tau (isoform 0N4R) was sequentially hyperphosphorylated using protein kinase A with either glycogen synthase kinase 3β or stress-activated protein kinase 4.
  • Tandem mass spectrometry identified phosphorylation sites.
  • High-resolution native mass spectrometry quantified the degree of phosphorylation.
  • Super-resolution and electron microscopy characterized aggregate morphology.
  • Functional assays assessed membrane disruption and Toll-like receptor 4 (TLR4)-dependent responses in human macrophages.

Main Results:

  • Sequential hyperphosphorylation enabled spontaneous polymerization of tau into small amorphous aggregates in vitro.
  • Hyperphosphorylated tau aggregates exhibited enhanced membrane disruption compared to unmodified aggregates.
  • These aggregates induced Toll-like receptor 4 (TLR4)-dependent inflammatory responses in human macrophages.

Conclusions:

  • Hyperphosphorylated tau can self-assemble into potentially damaging aggregates.
  • These aggregates promote neuroinflammation via TLR4-dependent pathways.
  • This provides a potential mechanism linking tau hyperphosphorylation to neuroinflammation in tauopathies.