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A central role for dityrosine crosslinking of Amyloid-ß in Alzheimer’s disease

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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 Serpell
Background 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

File Version

  • Published version

Journal

Acta Neuropathologica Communications

ISSN

2051-5960

Publisher

BioMed Central

Issue

83

Volume

1

Page range

1-17

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2014-04-30

First Open Access (FOA) Date

2014-04-30

First Compliant Deposit (FCD) Date

2014-04-30

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