Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking

Youssra K Al-Hilaly, Saskia J Pollack, Devkee Vadukul, Francesca Citossi, Janet E Rickard, Michael Simpson, John M D Storey, Charles R Harrington, Claude M Wischik, Louise C Serpell

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Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a C322A substitution. We show that disulphide bond formation inhibits assembly and that the C322A variant rapidly forms long and highly ordered PHFs.

Original languageEnglish
Pages (from-to)3650-3665
Number of pages16
JournalJournal of Molecular Biology
Issue number23
Early online date15 Sept 2017
Publication statusPublished - 24 Nov 2017

Bibliographical note

The authors would like to thank Dr. Pascale Schellenberger and Dr. Julian Thorpe for valuable help with TEM. TEM work was performed at the School of Life Sciences TEM imaging centre at the University of Sussex, which is supported by the Wellcome trust and RM Phillips.

LCS is supported by Alzheimer's Society and Alzheimer's Research UK Southcoast Network.


  • Journal Article
  • Alzheimer's disease
  • tau
  • neurofibrillary tangles
  • paired helical filaments
  • disulfide


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