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 (Aβ), the toxic effects of Aβ(31–35) and Aβ(25–35) peptides on isolated rat brain mitochondria were investigated. The results show that exposure of isolated rat brain mitochondria to Aβ(31–35) and Aβ(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 Aβ(31–35)Met35 OX in which methionine-35 was oxidized to methionine sulfoxide. The Aβ peptide derivative with norleucine substituting Met-35, i.e., Aβ(31–35)Nle-35, had not effect on any of the biochemical parameters tested. We have further characterized the action of Aβ(31–35) and Aβ(25–35) peptides on neuronal cells. Taken together our result indicate that Aβ(31–35) and Aβ(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.