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

Maina, Mahmoud B, Burra, Gunasekhar, Al-Hilaly, Youssra, Mengham, Kurtis, Fennell, Kate and Serpell, Louise C (2020) Metal- and UV- catalyzed oxidation results in trapped amyloid-β intermediates revealing that self-assembly is required for Aβ-induced cytotoxicity. iScience, 23 (10). a101537. ISSN 2589-0042

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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.

Item Type: Article
Keywords: Biochemical Mechanism, Molecular Neuroscience, Neurotoxicology
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Neuroscience
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 17 Sep 2021 13:16
Last Modified: 17 Sep 2021 13:30
URI: http://sro.sussex.ac.uk/id/eprint/101719

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