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

Abstract

Myeloperoxidase, the enzyme that produces hypochlorite (OCl-), is expressed by brain-resident immune cells and neurons. 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 internalization assays show that hypochlorite-induced modification of Aβ1-42 reduces its binding to the surface of SH-SY5Y cells and concomitantly, increases the efficiency of Aβ1-42 endocytosis. Our data is consistent with a model in which tightly regulated production of hypochlorite in the brain is protective against Aβ-induced toxicity.