Dityrosine Cross-links are Present in Alzheimer's Disease-derived Tau Oligomers and Paired Helical Filaments (PHF) which Promotes the Stability of the PHF-core Tau (297–391) In Vitro

Mahmoud B. Maina, Youssra K. Al-Hilaly, Sebastian Oakley, Gunasekhar Burra, Tahmida Khanom, Luca Biasetti, Kurtis Mengham, Karen Marshall, Charles R. Harrington, Claude M. Wischik, Louise C. Serpell*

*Corresponding author for this work

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A characteristic hallmark of Alzheimer's Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility. Dityrosine cross-linking has been shown in Aβ plaques in AD and α-synuclein aggregates in Lewy bodies in ex vivo tissue sections, and this modification may increase the insolubility of these aggregates and their resistance to degradation. Using the PHF-core tau fragment (residues 297 – 391) as a model, we have previously demonstrated that dityrosine formation traps tau assemblies to reduce further elongation. However, it is unknown whether dityrosine crosslinks are found in tau deposits in vivo in AD and its relevance to disease mechanism is unclear. Here, using transmission electron microscope (TEM) double immunogold-labelling, we reveal that neurofibrillary NFTs in AD are heavily decorated with dityrosine crosslinks alongside tau. Single immunogold-labelling TEM and fluorescence spectroscopy revealed the presence of dityrosine on AD brain-derived tau oligomers and fibrils. Using the tau (297–391) PHF-core fragment as a model, we further showed that prefibrillar tau species are more amenable to dityrosine crosslinking than tau fibrils. Dityrosine formation results in heat and SDS stability of oxidised prefibrillar and fibrillar tau assemblies. This finding has implications for understanding the mechanism governing the insolubility and toxicity of tau assemblies in vivo.

Original languageEnglish
Article number167785
Number of pages14
JournalJournal of Molecular Biology
Issue number19
Early online date15 Sept 2022
Publication statusPublished - 15 Oct 2022

Bibliographical note

The authors are grateful to M Goedert (MRC Laboratory of Molecular Biology, Cambridge, UK) for ex-vivo paired helical filaments which were kindly contributed by Bernandino Ghetti (Indiana University, USA). The authors are very grateful to Urmi Sengupta, Nemil Bhatt and Rakez Kayed (University of Texas, USA) for providing ex-vivo tau oligomers. TEM work was performed at the University of Sussex’s Electron microscopy imaging centre (EMC), funded by the School of Life Sciences, the Wellcome Trust (095605/Z/11/A, 208348/Z/17/Z) and the RM Phillips Trust. The authors thank Dr Pascale Schellenberger for valuable support.

This work was supported by funding from Alzheimer’s Society [AS-PG-16b-010] awarded to LCS and funding MBM. MBM is funded by the Alzheimer’s Association. YA is supported by WisTa Laboratories Ltd (PAR1596). The work was supported by ARUK South Coast Network. GB was supported by European Molecular Biology Organisation (EMBO) Short-Term Fellowship award (EMBO-STF 7674). LCS is supported by BBSRC [BB/S003657/1]. Urmi Sengupta, Nemil Bhatt, Rakez Kayed acknowledge the funding that supports their contribution (NIH grants to R.K: R01 AG054025 and U24AG072458).


  • Alzheimer's disease
  • dityrosine
  • oxidative stress
  • paired helical filaments
  • tau


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