Aβ(31–35) and Aβ(25–35) fragments of amyloid beta‐protein induce cellular death through apoptotic signals: Role of the redox state of methionine‐35

Abstract

In order to clarify the basis of neuronal toxicity exerted by the shortest active peptides of amyloid beta-protein (Abeta), the toxic effects of Abeta(31-35) and Abeta(25-35) peptides on isolated rat brain mitochondria were investigated. The results show that exposure of isolated rat brain mitochondria to Abeta(31-35) and Abeta(25-35) peptides determines: (i) release of cytochrome c; (ii) mitochondrial swelling and (iii) a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events resulted attenuated in isolated brain mitochondria exposed to the Abeta(31-35)Met35(OX) in which methionine-35 was oxidized to methionine sulfoxide. The Abeta peptide derivative with norleucine substituting Met-35, i.e., Abeta(31-35)Nle-35, had not effect on any of the biochemical parameters tested. We have further characterized the action of Abeta(31-35) and Abeta(25-35) peptides on neuronal cells. Taken together our result indicate that Abeta(31-35) and Abeta(25-35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals. Such a mechanism of toxicity seems to be dependent by the redox state of methionine-35.