Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis.
The p3 peptide [amyloid beta-peptide (Abeta) 17-40/42], derived by alpha- and gamma-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer's disease and cerebellar pre-amyloid in Down's syndrome. However, the importance of p3 peptide accumulation in Alzheimer's disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with Abeta 17-42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Abeta 17-42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked Abeta 17-42-induced neuronal death. Abeta 17-42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against Abeta 17-42 induced neuronal death. These results demonstrate that Abeta 17-42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Abeta 17-42. We propose that Abeta 17-42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer's disease.
Wei
Wanli
W
Molecular Neurobiology Unit, Laboratory of Cellular and Molecular Biology, Intramural Research Program, National Institute on Aging/NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA. wanliwei@hotmail.com
Norton
Darrell D
DD
Wang
Xiantao
X
Kusiak
John W
JW
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C086839:amyloid beta-protein (17-42); D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases