A central role for dityrosine crosslinking of Amyloid-β in Alzheimer's disease

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 (A beta) fibrils. Copper has been implicated to play a role in Alzheimer's disease. Dimers of A beta have been isolated from AD brain and have been shown to be neurotoxic. Results: We have investigated the formation of dityrosine cross-links in A beta 42 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 A beta oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized A beta in cell cultures treated with oligomeric A beta 42 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: A beta 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 A beta and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD.