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

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 to occur in vivo in Aβ plaques and α-synuclein aggregates in Lewy bodies, 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.

• Publication year

  2022

• Venue

  bioRxiv

• Publication date

  2022-05-28

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1101/2022.05.28.493839PMID 35961386
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A thiol-based intramolecular redox switch in four-repeat tau controls fibril assembly and disassembly

  2021cited by this paper
• Structural Identification of Individual Helical Amyloid Filaments by Integration of Cryo-Electron Microscopy-Derived Maps in Comparative Morphometric Atomic Force Microscopy Image Analysis

  2021cited by this paper
• Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

  2021cited by this paper
• Structure-based classification of tauopathies

  2021cited by this paper
• Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates

  2021influential reference
• Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

  2021cited by this paper
• Oxidative stress conditions result in trapping of PHF-core tau (297-391) intermediates

  2020influential reference
• Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

  2020cited by this paper
• Paired Helical Filament-Forming Region of Tau (297–391) Influences Endogenous Tau Protein and Accumulates in Acidic Compartments in Human Neuronal Cells

  2020cited by this paper
• Modulating disease-relevant tau oligomeric strains by small molecules

  2020cited by this paper
• Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity

  2020cited by this paper
• Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target

  2020cited by this paper
• Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease

  2019cited by this paper
• Tau (297‐391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer’s disease brain

  2019cited by this paper
• Pathological Tau From Alzheimer’s Brain Induces Site-Specific Hyperphosphorylation and SDS- and Reducing Agent-Resistant Aggregation of Tau in vivo

  2019cited by this paper
• Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT).

  2018cited by this paper
• Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases

  2018cited by this paper
• The involvement of tau in nucleolar transcription and the stress response

  2018cited by this paper
• Atypical, non-standard functions of the microtubule associated Tau protein

  2017cited by this paper
• Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking.

  2017influential reference
• Cryo-EM structures of Tau filaments from Alzheimer’s disease brain

  2017cited by this paper
• Nuclear Tau and Its Potential Role in Alzheimer’s Disease

  2016cited by this paper
• The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease

  2016cited by this paper
• Dityrosine, a protein product of oxidative stress, as a possible marker of acute myocardial infarctions

  2014cited by this paper
• A central role for dityrosine crosslinking of Amyloid-β in Alzheimer’s disease

  2013cited by this paper
• Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau

  2012cited by this paper
• Post-translational modifications of tau protein: implications for Alzheimer's disease.

  2011cited by this paper
• Tau Phosphorylated at Tyrosine 394 is Found in Alzheimer's Disease Tangles and can be a Product of the Abl-Related Kinase, Arg

  2010cited by this paper
• Nuclear Tau, a Key Player in Neuronal DNA Protection*

  2010cited by this paper
• The Microtubule-Associated Protein Tau is Also Phosphorylated on Tyrosine

  2009cited by this paper
• Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms.

  2006cited by this paper
• Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer's disease.

  2005cited by this paper
• Synthesis of the side chain cross-linked tyrosine oligomers dityrosine, trityrosine, and pulcherosine.

  2005cited by this paper
• Site-specific nitration differentially influences tau assembly in vitro.

  2005cited by this paper
• Cysteine Oxidation of Tau and Microtubule-associated Protein-2 by Peroxynitrite

  2004cited by this paper
• Copper mediates dityrosine cross-linking of Alzheimer's amyloid-beta.

  2004cited by this paper
• Pseudophosphorylation and Glycation of Tau Protein Enhance but Do Not Trigger Fibrillization in Vitro*

  2004cited by this paper
• Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease

  2003cited by this paper
• Oxidative Damage Is the Earliest Event in Alzheimer Disease

  2001cited by this paper
• Myeloperoxidase and protein oxidation in cystic fibrosis.

  2000cited by this paper
• Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies.

  2000cited by this paper
• An immunochemical study on tau glycation in paired helical filaments.

  1999cited by this paper
• In vitro peroxidase oxidation induces stable dimers of beta-amyloid (1-42) through dityrosine bridge formation.

  1999cited by this paper
• Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules

  1996cited by this paper
• Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.

  1995cited by this paper
• Dityrosine: a marker for oxidatively modified proteins and selective proteolysis.

  1994cited by this paper
• AGGREGATION OF COLLAGEN EXPOSED TO UVA IN THE PRESENCE OF RIBOFLAVIN: A PLAUSIBLE ROLE OF TYROSINE MODIFICATION

  1994cited by this paper
• Oxidized amino acids in lens protein with age. Measurement of o-tyrosine and dityrosine in the aging human lens.

  1993cited by this paper
• Dityrosine and tyrosine oxidation products are endogenous markers for the selective proteolysis of oxidatively modified red blood cell hemoglobin by (the 19 S) proteasome.

  1993cited by this paper
• A68: a major subunit of paired helical filaments and derivatized forms of normal Tau.

  1991cited by this paper
• A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis.

  1990cited by this paper
• Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.

  1988cited by this paper
• The carboxyl third of tau is tightly bound to paired helical filaments.

  1988cited by this paper
• Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.

  1986cited by this paper
• Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease.

  1986cited by this paper
• Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study.

  1985cited by this paper
• The rapid H2O2-mediated nonphotodynamic crosslinking of lens crystallins generated by the heme-undecapeptide from cytochrome C: potential implications for cataractogenesis in man.

  1983cited by this paper
• Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly.

  1977cited by this paper
• Dityrosine in collagen.

  1976cited by this paper
• Occurrence of dityrosine in cuticlin, a structural protein from Ascaris cuticle

  1975cited by this paper
• A protein factor essential for microtubule assembly.

  1975cited by this paper
• Occurrence of dityrosine in Tussah silk fibroin and keratin.

  1971cited by this paper
• Evidence for dityrosine in elastin.

  1967cited by this paper
• The oxidation of tyramine, tyrosine, and related compounds by peroxidase.

  1959cited by this paper

• Harnessing estrogen's neuroprotective potential in mitigating Alzheimer's pathologies in postmenopausal women: a review.

  2026cites this paper
• Chemical repair of oxidized aromatic amino acids by monohydroxylated 2-pyridones.

  2026cites this paper
• Cold plasma-induced amyloid fibrils of β-Lactoglobulin: Structural modulation, antigenicity reduction, and emulsification enhancement.

  2026cites this paper
• Pathological Disulfide Bond Crosslinking: Molecular Insights into Amyloidogenesis and Diseases Progression

  2025cites this paper
• Peroxynitrite-induced structural alterations render human fibrinogen more immunogenic: A possible mechanism of auto-immune response that acts as a proatherogenic marker.

  2025cites this paper
• Prions and protein aggregates as pathogens, self-propagating structures, biomarkers, and therapeutic targets

  2025cites this paper
• Tyrosine - a structural glue for hierarchical protein assembly.

  2024cites this paper
• Broken but not beaten: Challenge of reducing the amyloids pathogenicity by degradation

  2024cites this paper
• Influence of blocking groups on photo-oxidation of tyrosine and derivatives

  2024cites this paper
• Effect and mechanism of acupuncture on Alzheimer’s disease: A review

  2023cites this paper
• Tau; One Protein, So Many Diseases

  2023cites this paper
• Recent Computational Advances Regarding Amyloid-β and Tau Membrane Interactions in Alzheimer’s Disease

  2023cites this paper
• Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway.

  2023cites this paper
• Dityrosine cross-linking and its potential roles in Alzheimer’s disease

  2023cites this paper
• Shapeshifting tau: from intrinsically disordered to paired-helical filaments

  2022cites this paper
• New TEMPO–Appended 2,2′-Bipyridine-Based Eu(III), Tb(III), Gd(III) and Sm(III) Complexes: Synthesis, Photophysical Studies and Testing Photoluminescence-Based Bioimaging Abilities

  2022cites this paper
• Promoting ovalbumin amyloid fibrils formation by cold plasma treatment and improving its emulsifying properties

  year unknowncites this paper