Serpell.pdf (1.93 MB)
A central role for dityrosine crosslinking of Amyloid-ß in Alzheimer’s disease
journal contribution
posted on 2023-06-08, 17:06 authored by Youssra Al-Hilaly, Thomas L Williams, Maris Stewart-Parker, Lenzie Ford, Eldhose Skaria, Michael Cole, William Bucher, Kyle L Morris, Alaa Sada, Julian R Thorpe, Louise SerpellLouise SerpellBackground Alzheimer’s disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aß) fibrils. Copper has been implicated to play a role in Alzheimer’s disease. Dimers of Aß have been isolated from AD brain and have been shown to be neurotoxic. Results We have investigated the formation of dityrosine cross-links in Aß42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aß oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aß in cell cultures treated with oligomeric Aß42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients. Conclusions Aß dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer’s disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aß and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD.
Funding
BBSRC; Maris Stewart-Parker
History
Publication status
- Published
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- Published version
Journal
Acta Neuropathologica CommunicationsISSN
2051-5960Publisher
BioMed CentralExternal DOI
Issue
83Volume
1Page range
1-17Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2014-04-30First Open Access (FOA) Date
2014-04-30First Compliant Deposit (FCD) Date
2014-04-30Usage metrics
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