Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297-391) Intermediates.

Mahmoud B Maina,Charles R Harrington,Gunasekhar Burra,Claude M Wischik,Louise C Serpell,Janet E Rickard,Youssra K Al-Hilaly

doi:10.3390/cells10030703

Abstract

The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer’s disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links. Previous studies have revealed that metal-catalysed oxidation (MCO) using Cu2+ and H2O2 leads to the formation of DiY cross-links in two misfolding proteins, Aβ and α-synuclein, associated with AD and Parkinson’s disease respectively. The effect of MCO on tau remains unknown. Here, we examined the effect of MCO and ultra-violet oxidation to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers that fail to bind thioflavin S, lack β-sheet structure and prevents their elongation into filaments. At a higher concentration, Cu2+ (without H2O2) also facilitates the formation of these tau oligomers. The DiY cross-linked tau oligomers do not cause cell death. Our findings suggest that DiY cross-linking of pre-assembled tau promotes the formation of soluble tau oligomers that show no acute impact on cell viability.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, characterised by the deposition of extracellular amyloid-beta (Aβ) plaques and accumulation of intracellular neurofibrillary tangles (NFTs)
The burden of NFTs is correlated with the extent of pathology in AD [3], and NFT accumulation provides a reliable staging of the disease process [4]
The control sample, dGAE incubated with Cu2+ at a ratio of 1:0.1 alone [1-0.1/Cu2+ ] or additional 2.5 mM H2 O2 (1-0.1/Cu2+ H2 O2 ) and dGAE with ethylenediaminetetraacetic acid (EDTA) alone at 1:1000 ratio (1-1000 EDTA) showed no signal intensity at 405 nm (Figure 1A)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, characterised by the deposition of extracellular amyloid-beta (Aβ) plaques and accumulation of intracellular neurofibrillary tangles (NFTs). NFTs are comprised of paired helical filaments (PHFs) and straight filaments (SFs) composed of tau [1,2]. The burden of NFTs is correlated with the extent of pathology in AD [3], and NFT accumulation provides a reliable staging of the disease process [4]. Some types of oligomers are likely to convert to PHFs and SFs [5]. Tau oligomers have been identified in the early stages of AD [10]

Methods

Results

Conclusion