Paired helical filament forming region of tau (297-391) influences endogenous tau protein and accumulates in acidic compartments in human neuronal cells

Saskia J. Pollack, Jasmine Trigg, Tahmida Khanom, Luca Biasetti, Karen E. Marshall, Youssra K. Al-Hilaly, Janet E. Rickard, Charles R. Harrington, Claude M. Wischik, Louise C. Serpell* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Assembly of tau protein into paired helical filaments and straight filaments is a key feature of Alzheimer's disease. Aggregation of tau has been implicated in neurodegeneration, cellular toxicity and the propagation, which accompanies disease progression. We have reported previously that a region of tau (297–391), referred to as dGAE, assembles spontaneously in physiological conditions to form paired helical filament-like fibres in vitro in the absence of additives such as heparin. This provides a valuable tool with which to explore the effects of tau in cell culture. Here we have studied the cellular uptake of soluble oligomeric and fibrillar forms of dGAE and examined the downstream consequences of tau internalisation into differentiated SH-SY5Y neuroblastoma cells using fluorescence and electron microscopy alongside structural and biochemical analyses. The assembled dGAE shows more acute cytotoxicity than the soluble, non-aggregated form. Conversely, the soluble form is much more readily internalised and, once within the cell, is able to associate with endogenous tau resulting in increased phosphorylation and aggregation of endogenous tau, which accumulates in lysosomal/endosomal compartments. It appears that soluble oligomeric forms are able to propagate tau pathology without being acutely toxic. The model system we have developed now permits the molecular mechanisms of propagation of tau pathology to be studied in vitro in a more physiological manner with a view to development of novel therapeutic approaches.

Original languageEnglish
Pages (from-to)4891-4907
Number of pages17
JournalJournal of Molecular Biology
Volume432
Issue number17
Early online date16 Jul 2020
DOIs
Publication statusPublished - 7 Aug 2020

Keywords

  • tau
  • Alzheimer’s disease
  • propagation
  • aggregation
  • Alzheimer's disease
  • ALZHEIMERS-DISEASE
  • TAUOPATHY
  • PATHOLOGY
  • AUTOPHAGY
  • OLIGOMERS
  • IN-VITRO
  • FIBRILS
  • PROPAGATION
  • AGGREGATION
  • SYNTHETIC TAU

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