NAC peptide evoked oxidative stress leads to p53 mediated apoptosis

• Autorzy: Kazmierczak A. , Czapski G.A. , Adamczyk A. , Strosznajder J.B.
• Języki publikacji: EN

Abstrakty

EN

The non-Aβ component of Alzheimer’s disease (AD) amyloid (NAC) is a highly amyloidogenic peptide consisting of 35 amino acids which was first identified associated with senile plaques in AD brain. It is a fragment of the presynaptic protein alpha-synuclein and, as such, it is implicated in the etiologies of both Alzheimer’s and Parkinson’s (PD) disease. However the molecular mechanisms of NAC toxicity is not fully understood. Our present study focused on the role of oxidative stress mediated p53 pathway in apoptotic cell death evoked by NAC peptide. Here we found that exposure of PC12 cells to exogenous NAC peptide (10 µM) enhanced free radical generation, induced mitochondria dysfunction and cell death. We also observed free radicals-dependent enhancement of Tp53 gene expression after NAC treatment. The inhibition of p53 by pifithrin significantly protected PC12 cells against NAC peptide - evoked mitochondria failure and death. In addition, exposure to NAC peptide resulted in the higher expression of cyclin-dependent kinase 5 (Cdk5), one of the enzymes responsible for p53 phosphorylation and activation. Concomitantly, we observed the increase of expression of Cdk5r1 and Cdk5r2 genes, coding p35 and p39 peptides, that are essential co-factors in regulation of Cdk5 activity. Moreover, the specific Cdk5 inhibitor (BML-259, 10µM) protected large population of cells against NAC-evoked cell death. Our findings indicate that NAC peptide exerts its toxic effect by activation of p53/Cdk5 - dependent apoptotic signaling pathway. This study was supported by MSHE Grant NN 401024236 and statutory theme no 7.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: 1
• Opis fizyczny: p.165

Twórcy

autor

Kazmierczak A.

• Mossakowski Medical Research Centre, Department of Cellular Signalling, Polish Academy of Sciences, Warsaw, Poland

autor

Czapski G.A.

• Mossakowski Medical Research Centre, Department of Cellular Signalling, Polish Academy of Sciences, Warsaw, Poland

autor

Adamczyk A.

• Mossakowski Medical Research Centre, Department of Cellular Signalling, Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder J.B.

• Mossakowski Medical Research Centre, Department of Cellular Signalling, Polish Academy of Sciences, Warsaw, Poland