H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK.
Amyloid beta peptides (Abeta) may be neurotoxic during the progression of Alzheimer's disease by eliciting oxidative stress. Exposure of neuronally differentiated SK-N-BE cells to Abeta(25-35) fragment as well as to full-length Abeta(1-40) and Abeta(1-42) induces early and time-dependent generation of oxidative stress that has been evaluated by carefully monitoring generation of hydrogen peroxide (H(2)O(2)), 4-hydroxynonenal (HNE), thiobarbituric acid reactive substances (TBARS), and fluorescent chromolipids. Abeta treatment also results in the activation of c-Jun aminoterminal kinases (JNKs) and p38(MAPK) and is followed by characteristic nuclear changes of apoptosis as evaluated by DAPI staining and TUNEL technique. To reproduce the relationships between oxidative stress and Abeta apoptosis we found that only the simultaneous administration of HNE and H(2)O(2), at concentrations similar to those generated within the first 3 h of Abeta exposure, can fully mimic Abeta-dependent activation of JNKs and p38(MAPK) and occurrence of apoptosis. Antioxidants such as alpha-tocopherol and N-acetylcysteine prevent completely either neuronal apoptosis or activation of JNKs and p38(MAPK) elicited by Abeta or by simultaneous HNE and H(2)O(2) addition. Finally, direct evidence that activation of these kinases is required for cell death induced by Abeta has been obtained by pretreating cell with specific inhibitors of JNKs and p38(MAPK). These results suggest the existence of a sequence of events in Abeta-induced apoptosis involving simultaneous generation of HNE and H(2)O(2) and oxidative stress-dependent activation of JNKs and p38(MAPK).
Tamagno
E
E
Department of Experimental Medicine and Oncology, General Pathology Section, Corso Raffaello 30, University of Turin, 10125 Turin, Italy. elena.tamagno@unito.it
Robino
G
G
Obbili
A
A
Bardini
P
P
Aragno
M
M
Parola
M
M
Danni
O
O
D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal