Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 58, Issue 2, Pages 206-214Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2010.11.018
Keywords
alpha-Synuclein; Non-A beta component of Alzheimer's disease; amyloid protein; p53 protein; Cyclin-dependent kinase 5; Neuronal Cdk5 activator (p25-p35); Cdk5 activator p39; Oxidative stress; Apoptosis; Bax protein
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Funding
- Ministry of Science and Higher Education [NN401 014635]
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The non-A beta component of Alzheimer's disease (AD) amyloid (NAC) is produced from the precursor protein NACP/alpha-synuclein (ASN) by till now unknown mechanism. Previous study showed that like ASN, NAC peptide induced oxidative/nitrosative stress and apoptosis. Our present study focused on the mechanisms of PC12 cells death evoked by NAC peptide, with particular consideration on the role of p53 protein. On the basis of molecular and transmission electron microscopic (TEM) analysis it was found that exogenous NAC peptide (10 mu M) caused mitochondria dysfunction, enhanced free radical generation, and induced both apoptotic and autophagic cell death. Morphological and immunocytochemical evidence from TEM showed marked changes in expression and in translocation of proapoptotic protein Bax. We also observed time-dependent enhancement of Tp53 gene expression after NAC treatment. Free radicals scavenger N-tert-butyl-alpha-phenylnitrone (PBN, 1 mM) and p53 inhibitor (alpha-Pifithrin, 20 mu M) significantly protected PC12 cells against NAC peptide-evoked cell death. In addition, exposure to NAC peptide resulted in 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 regulators of Cdk5 activity. Moreover, the specific Cdk5 inhibitor (BML-259, 10 mu M) 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 and Bax-dependent apoptotic signaling pathway. (C) 2010 Elsevier Ltd. All rights reserved.
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