Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42

Noralyn B. Mañucat-Tan, Ashfaq Chowdhury, Rodrigo Cataldi, Rafaa Zeineddine Abdullah, Janet R. Kumita, Amy R. Wyatt

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
55 Downloads (Pure)

Abstract

Exacerbated hypochlorite (OCl-) production is linked to neurodegenerative processes, but there is growing evidence that lower levels of hypochlorite activity are important to protein homeostasis. In this study we characterise the effects of hypochlorite on the aggregation and toxicity of amyloid beta peptide 1-42 (Aβ1-42), a major component of amyloid plaques that form in the brain in Alzheimer's disease. Our results demonstrate that treatment with hypochlorite promotes the formation of Aβ1-42 assemblies ≥100 kDa that have reduced surface exposed hydrophobicity compared to the untreated peptide. This effect is the result of the oxidation of Aβ1-42 at a single site as determined by mass spectrometry analysis. Although treatment with hypochlorite promotes the aggregation of Aβ1-42, the solubility of the peptide is enhanced and amyloid fibril formation is inhibited as assessed by filter trap assay, thioflavin T assay and transmission electron microscopy. The results of in vitro assays using SH-SY5Y neuroblastoma cells show that pre-treatment of Aβ1-42 with a sub-stoichiometric amount of hypochlorite substantially reduces its toxicity. The results of flow cytometry analysis and internalisation assays indicate that hypochlorite-induced modification of Aβ1-42 reduces its toxicity via at least two-distinct mechanism, reducing the total binding of Aβ1-42 to the surface of cells and facilitating the cell surface clearance of Aβ1-42 to lysosomes. Our data is consistent with a model in which tightly regulated production of hypochlorite in the brain is protective against Aβ-induced toxicity.
Original languageEnglish
Article number102736
Number of pages10
JournalRedox Biology
Volume63
Early online date13 May 2023
DOIs
Publication statusPublished - Jul 2023

Keywords

  • protein misfolding
  • Alzheimer’s Disease
  • oxidative stress
  • Renewable energy
  • inflammation
  • post-translational modification

Fingerprint

Dive into the research topics of 'Hypochlorite-induced oxidation promotes aggregation and reduces toxicity of amyloid beta 1-42'. Together they form a unique fingerprint.

Cite this