Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity

Mahmoud B Maina; Gunasekhar Burra; Youssra K Al-Hilaly; Kurtis Mengham; Kate Fennell; Louise C Serpell

doi:10.1016/j.isci.2020.101537

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity

iScience. 2020 Sep 6;23(10):101537. doi: 10.1016/j.isci.2020.101537. eCollection 2020 Oct 23.

Authors

Mahmoud B Maina^{1

2}, Gunasekhar Burra¹, Youssra K Al-Hilaly^{1

3}, Kurtis Mengham¹, Kate Fennell¹, Louise C Serpell¹

Affiliations

¹ Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QG, UK.
² College of Medical Sciences, Yobe State University, Yobe, Nigeria.
³ Chemistry Department, College of Science, Mustansiriyah University, Baghdad, Iraq.

Abstract

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-β (Aβ) forms DiY in vitro and DiY-cross-linked Aβ is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aβ42 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 Aβ42 (vAβ) with wild-type Aβ42. Oxidation results in the formation of trapped wild-type Aβ assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vAβ and trapped Aβ assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked Aβ. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped Aβ assemblies and assembly-incompetent variant Aβ are unable to result in cell death.

Keywords: Biochemical Mechanism; Molecular Neuroscience; Neurotoxicology.

Grants and funding

MR/K022105/1/MRC_/Medical Research Council/United Kingdom