Subscribe Now Subscribe Today
Fulltext PDF
Research Article
Aß(25-35) Peptide Induces Cell Death in PC12 Cells via Mitochondrial Damage and Cytochrome c Release

Cristiana Carelli Alinovi , Michela Pezzotti , Daniele Mezzogori , M. Elisabetta Clementi , Francesco Misiti , Bruno Giardina and Federica Orsini

The pathological features of Alzheimer`s disease include deposition of senile plaques in different brain zones formed by aggregates of fibrillar Aß peptide (AßP), a neurotoxic metabolic product. In this study we used the soluble form of fragment 25-35 of AßP, that includes methionine 35, side chain of AßP, to investigate the role of redox state of Met-35 on the pathogenesis of AD, because this residue in AßP is the most susceptible to oxidation in vivo. The data obtained evidenced that Aß(25-35) peptide determines a loss of PC12 cells viability determining mitochondrial damage with a possible trigger of pro-apoptotic signals. In particular, the following parameters were examined: cytochrome c release, mitochondrial membrane potential (ΔΨm) and mitochondrial respiration. In this study, three different peptides have been used: Aß(25-35) with methionine 35 in the reduced state, oxidized to sulfoxide and/or substituted with norleucine. We conclude that alteration in the mitochondrial functionality might be a contributing factor to the pathogenesis of AD and the amplitude of the effects elicited by Aß peptide is modulated by the redox state of methionine.

Related Articles in ASCI
Similar Articles in this Journal
Search in Google Scholar
View Citation
Report Citation

  How to cite this article:

Cristiana Carelli Alinovi , Michela Pezzotti , Daniele Mezzogori , M. Elisabetta Clementi , Francesco Misiti , Bruno Giardina and Federica Orsini , 2006. Aß(25-35) Peptide Induces Cell Death in PC12 Cells via Mitochondrial Damage and Cytochrome c Release . Journal of Biological Sciences, 6: 140-145.

DOI: 10.3923/jbs.2006.140.145


Boland, K., M. Behrens, D. Choi, K. Manias and D.H. Perlmutter, 1996. The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide. J. Biol. Chem., 271: 18032-18044.
CrossRef  |  

Buchet, R., E. Tavitian, D. Ristig, R. Swoboda, U. Stauss and H.U. Gremlich, 1996. Conformation of synthetic β peptides in solid state and in aqueous solution relation to toxicity in PC12 cells. Biochem. Biophys. Acta, 1315: 40-46.
CrossRef  |  

Cardoso, S.M., R.H. Swerdlow and C.R. Oliveira, 2002. Induction of cytochrome c mediated apoptosis by amyloid β 25-35 requires functional mitochondria. Brain. Res., 931: 117-125.
Direct Link  |  

Casley, C.S, J.M. Land, M.A. Sharpe, J.B. Clark, M.R. Duchen and L. Canevari, 2002. β amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol. Dis., 10: 258-267.

Clementi, M.E., G.E. Martorana, M. Pezzotti, B. Giardina and F. Misiti, 2004. Methionine 35 oxidation reduces toxic effects of the amyloid β protein fragment (31-35) on human red blood cell. Int. J. Biochem. Cell Biol., 36: 2066-2076.
CrossRef  |  

Cory, A.H., T.C. Owen, J.A. Barltrop and J.G. Cory, 1991. Use of an aqueous soluble tetrazolium formazan assay for cell growth assays in culture. Cancer. Commun., 3: 207-212.
PubMed  |  

Dahlgren, K.N., A.M. Manelli, W.B.Jr. Stine, L.K. Baker, G.A. Krafft and M.J. LaDu, 2002. Oligomeric and fibrillar species of amyloid β peptides differentially affect neuronal viability. J. Biol. Chem., 277: 32046-32053.
Direct Link  |  

Green, D.R. and J.C. Reed, 1998. Mitochondria and apoptosis. Science, 281: 1309-1312.
CrossRef  |  PubMed  |  Direct Link  |  

Hong, J. and C. Schoneich, 2001. The metal catalyzed oxidation of methionine in peptides by fenton systems involves two consecutive one electron oxidation processes. Free Radic. Biol. Med., 31: 1342-1441.
PubMed  |  

Iuvone, T., G. Esposito, R. Esposito, R. Santamaria, M.D. Rosa and A.A. Izzo, 2004. Neuroprotective effect of cannabidiol a non psychoactive component from Cannabis sativa on β amyloid induced toxicity in PC12 cells. J. Neorochem., 89: 134-141.
Direct Link  |  

Kim, H.S., J.H. Lee, J.P. Lee, E.M. Kim and K.A. Chang et al., 2002. Amyloid β peptide induces cytochrome c release from isolated mitochondria. Neuroreport., 13: 1989-1993.
Direct Link  |  

Kuo, Y.M., T.A. Kokjohn, T.G. Beach and L.I. Sue et al., 2001. Comparative analysis of amyloid β chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J. Biol. Chem., 276: 12991-12998.

Mattson, M.P., B. Cheng, D. David, K. Bryant, I. Leiberburg and R.E. Rydel, 1992. β amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neuroscience, 12: 376-389.
Direct Link  |  

Meei, H.H., F. Corinne, X. Hui, Z. Hui and G.E. Gibson, 2004. Mitochondrial function in fibroblasts with aging in culture and or Alzheimers disease. Neurobiol. Aging, 26: 839-848.

Misiti, F., B. Sampaolese, M. Pezzotti, S. Marini and M.E. Clementi et al., 2005. Aβ (31-35) peptide induces apoptosis in PC12 cells contrast with Aβ (25-35) peptide and examination of underlying mechanisms. Neurochem. Int., 46: 575-583.
Direct Link  |  

Misiti, F., G.E. Martorana, G. Nocca, E. Di Stasio, B. Giardina and M.E. Clementi, 2004. Methionine 35 oxidation reduces toxic and pro-apoptotic effects af the amyloid beta-protein fragment (31-35) on isolated brain mitochondria. Neuroscience, 126: 297-303.
CrossRef  |  Direct Link  |  

Nicholls, D.G. and S.L. Budd, 2000. Mitochondria and neuronal survival. Physiol. Rev., 80: 315-360.
Direct Link  |  

Nista, E.C., M. Candelli, F. Cremonini, I.A. Cazzato and A. Gasbarrini et al., 2004. Bacillus clausii therapy to reduce side effects of anti Helicobacter pylori treatment randomized double blind placebo controlled trial. Ail. Pharmacol. Ther., 20: 1181-1188.
PubMed  |  

Pike, C.J., A.J.W. Wasserman, J. Kosmoski, D.H. Cribbs, C.G. Glabe and C.W. Cotman, 1995. Structure activity analyses of β amyloid peptides contributions of the β 25-35 region to aggregation and neurotoxicity. J. Neurochem., 64: 253-265.
Direct Link  |  

Pike, C.J., D. Burdick, A.J. Walencewicz, C.G. Glabe and C.W. Cotman, 1993. Neurodegeneration induced by β amyloid peptides In vitro the role of peptide assembly state. J. Neurosci., 13: 1676-1678.
Direct Link  |  

Preston, M.R., J.D. Estermyer, J. Kelly and P.E. Mason, 1996. Alzheimers disease amyloid β peptide 25-35 is localized in the membrane hydrocarbon core x ray diffraction analysis. Biochem. Biophys. Res. Commun., 222: 78-82.

Qiao, H., R.C. Koya, K. Nakagawa, H. Tanaka, H. Fujita, M. Takimoto and N. Kuzumaky, 2005. Inhibition of Alzheimers amyloid β peptide induced reduction of mitochondrial membrane potential and neurotoxicity by gelsolin. Neurobiol. Aging., 26: 849-855.
Direct Link  |  

Scaduto, R.C. and L.W. Grotyohann, 1999. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. J. Biophys., 76: 469-477.
Direct Link  |  

Smith, M.A., C.A. Rottkamp, A. Nunomura, A.K. Raina and G. Perry, 2000. Oxidative stress in Alzheimer's disease. Biochimica Biophysica Acta (BBA)-Mol. Basis Dis., 1502: 139-144.
CrossRef  |  PubMed  |  Direct Link  |  

Varadarajan, S., J. Kanski, M. Aksenova, C. Lauderback and D.A. Butterfield, 2001. Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's Aβ(1--42) and Aβ(25-35). J. Am.. Chem. Soc., 123: 5625-5631.
CrossRef  |  

Varadarajan, S., S. Yatin, M. Aksenova and D.A. Butterfield, 2000. Alzheimers amyloid β peptide associated free radical oxidative stress and neurotoxicity. J. Struct. Biol., 130: 184-208.

Watson, A.A., D.P. Fairlie and D.J. Craik, 1998. Solution structure of methionine oxidized amyloid β peptide (1-40) does oxidation affect conformational switching. Biochem., 37: 12700-12706.
CrossRef  |  

Wood, S.J., B. Maleeff, T. Hart and R. Wetzel, 1996. Physical morphological and functional differences between pH 5.8 and 7.4 aggregates of the Alzheimer's amyloid peptide Aβ. J. Mol. Biol., 256: 870-877.

Xiao, X.Q., H.Y. Zhang and X.C. Tang, 2002. Huperzine a attenuates amyloid β peptide fragment 25-35 induces apoptotic in rat cortical neurons via inhibiting reactive oxigen species formation and caspase 3activation. J. Neurosi. Res., 67: 30-36.
Direct Link  |  

©  2019 Science Alert. All Rights Reserved
Fulltext PDF References Abstract