Abstract
Current evidence suggests that amyloid beta peptides (Abeta) may play a major role in the pathogenesis of Alzheimer's disease by eliciting oxidative stress and neuronal apoptosis. In this study we have used differentiated SK-N-BE neurons to investigate molecular mechanisms and regulatory pathways underlying apoptotic neuronal cell death elicited by Abeta(1-40) and Abeta(1-42) peptides as well as the relationships between apoptosis and oxidative stress. Abeta peptides, used at concentrations able to induce oxidative stress, elicit a classic type of neuronal apoptosis involving mitochondrial regulatory proteins and pathways (i.e. affecting Bax and Bcl-2 protein levels as well as release of cytochrome c in the cytosol), poly-ADP rybose polymerase cleavage and activation of caspase 3. This pattern of neuronal apoptosis, that is significantly prevented by alpha-tocopherol and N-acetylcysteine and completely abolished by specific inhibitors of stress-activated protein kinases (SAPK) such as JNKs and p38(MAPK), involved early elevation of p53 protein levels. Pretreatment of neurons with alpha-pifithrin, a specific p53 inhibitor, resulted in a 50-60% prevention of Abeta induced apoptosis. These results suggest that oxidative stress - mediated neuronal apoptosis induced by amyloid beta operates by eliciting a SAPK-dependent multiple regulation of pro-apoptotic mitochondrial pathways involving both p53 and bcl-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Amyloid beta-Peptides / pharmacology*
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Apoptosis / drug effects*
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Benzothiazoles
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Caspase 3
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Caspases / metabolism
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Cell Differentiation
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Cytochromes c / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Humans
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Hydrogen Peroxide / metabolism
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Neuroblastoma / metabolism
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Neuroblastoma / pathology*
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Oxidative Stress / drug effects*
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Peptide Fragments / pharmacology*
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Thiazoles / pharmacology
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Toluene / analogs & derivatives*
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Toluene / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism
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alpha-Tocopherol / pharmacology
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bcl-2-Associated X Protein
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p38 Mitogen-Activated Protein Kinases
Substances
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Amyloid beta-Peptides
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BAX protein, human
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Benzothiazoles
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Enzyme Inhibitors
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Peptide Fragments
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Thiazoles
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Tumor Suppressor Protein p53
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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bcl-2-Associated X Protein
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Toluene
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Cytochromes c
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Hydrogen Peroxide
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pifithrin
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Poly(ADP-ribose) Polymerases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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alpha-Tocopherol
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Acetylcysteine