Metal- and UV- catalyzed oxidation results in trapped amyloid-ß intermediates revealing that self-assembly is required for Aß-induced cytotoxicity

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-ß (Aß) forms DiY in vitro and DiY-cross-linked Aß is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aß42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of Aß42 (vAß) with wild-type Aß42. Oxidation results in the formation of trapped wild-type Aß assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vAß and trapped Aß assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked Aß. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped Aß assemblies and assembly-incompetent variant Aß are unable to result in cell death.