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 (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.
Clementi
M Elisabetta
ME
Institute of Biochemistry and Clinical Biochemistry and CNR Institute Chimica del Riconoscimento Molecolare Faculty of Medicine, Catholic University Largo F. Vito 1, Rome, Italy. elisabetta.clement@icrm.cr.it
Marini
Stefano
S
Coletta
Massimo
M
Orsini
Federica
F
Giardina
Bruno
B
Misiti
Francesco
F
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D008297:Male; D008715:Methionine / Q000737:chemistry*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C113042:amyloid beta-protein (31-35); D008715:Methionine