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

In order to clarify the basis of neuronal toxicity exerted by the shortest active peptides of amyloid beta-protein (Ab), the toxic effects of Ab(31–35) and Ab(25–35) peptides on isolated rat brain mitochondria were investigated. The results show that exposure of isolated rat brain mitochondria to Ab(31–35) and Ab(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 Ab(31–35)Met35OX in which methionine- 35 was oxidized to methionine sulfoxide. The Ab peptide derivative with norleucine substituting Met-35, i.e., Ab(31–35)Nle-35, had not effect on any of the biochemical parameters tested. We have further characterized the action of Ab(31–35) and Ab(25–35) peptides on neuronal cells. Taken together our result indicate that Ab(31–35) and Ab(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 triggerof apoptotic signals. Such a mechanism of toxicity seems to be dependent by the redox state of methionine-35.