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01 November 2005

Substitution of methionine 35 inhibits apoptotic effects of Abeta(31-35) and Abeta(25-35) fragments of amyloid-beta protein in PC12 cells.

Maria Elisabetta Clementi, Francesco Misiti

Med Sci Monit 2005; 11(11): BR381-385 :: ID: 430276

Abstract

BACKGROUND: Amyloid-beta peptide (AbetaP), the central constituent of senile plaques in Alzheimer's disease (AD) brain, has been shown to be toxic to neuronal cells and that this toxicity is responsible for the progressive cognitive decline associated with this neurodegenerative disease. The precise mechanism of AbetaP action remains to be determined; however, it has been reported that the methionine residue at position 35 plays a pivotal role in the toxicity of the peptide. With this in mind, the present study examines the effect of mutating the methionine to norleucine in the fragments (31-35) and (25-35) of AbetaP, which have methionine at the C-terminal, in order to investigate the influence of this residue on Abeta-mediated toxic effects on PC12 cells. MATERIAL/METHODS: The toxic and apoptotic effects (release of Cyt c, caspase activation, and DNA fragmentation) exerted by the Abeta(31-35) and Abeta(25-35) wild-type peptides and Abeta(31-35)Met-->Nle, Abeta(25-35)Met-->Nle peptides where methionine was substituted with norleucine were investigated on PC12 cells. RESULTS: The results obtained shown that both peptides induce neurotoxicity in PC12 cells via an apoptotic cell death pathway, including cytochrome c release, caspase activation, and DNA fragmentation. Furthermore, this study reveals that these events were completely abrogated in cells exposed to Abeta peptides in which methionine 35 was substituted by a norleucine residue. CONCLUSIONS: On the basis of the results obtained in this study, an additional hypothesis involving the amyloid-beta peptide and the role of Met-35 has been proposed to clarify the mechanisms responsible of neurodegeneration in Alzheimer's disease.

Keywords: Amyloid beta-Peptides - toxicity, Amino Acid Substitution - genetics, Caspases - analysis, Cytochromes c - analysis, Methionine - genetics, Neurons - enzymology, Norleucine - genetics, PC12 Cells, Peptide Fragments - toxicity

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750