beta-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation.
beta-Amyloid (A beta) has been strongly implicated in the pathophysiology of Alzheimer's disease (AD), but the means by which the aggregated form of this molecule induces neuronal death have not been fully defined. Here, we examine the role of the c-Jun N-terminal kinases (JNKs) and of their substrate, c-Jun, in the death of cultured neuronal PC12 cells and sympathetic neurons evoked by exposure to aggregated A beta. The activities of JNK family members increased in neuronal PC12 cells within 2 h of A beta treatment and reached 3--4-fold elevation by 6 h. To test the role of these changes in death caused by A beta, we examined the effects of CEP-1347 (KT7515), an indolocarbazole that selectively blocks JNK activation. Inclusion of CEP-1347 (100--300 nM) in the culture medium effectively blocked the increases in cellular JNK activity caused by A beta and, at similar concentrations, protected both PC12 cells and sympathetic neurons from A beta-evoked-death. Effective protection required addition of CEP-1347 within 2 h of A beta treatment, indicating that the JNK pathway acts relatively proximally and as a trigger in the death mechanism. A dominant-negative c-Jun construct also conferred protection from A beta-evoked death, supporting a model in which JNK activation contributes to death via activation of c-Jun. Finally, CEP-1347 blocked A beta-stimulated activation of caspase-2 and -3, placing these downstream of JNK activation. These observations implicate the JNK pathway as a required element in death evoked by A beta and hence identify it as a potential therapeutic target in AD.
Troy
C M
CM
Department of Pathology, Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York 10032, USA. cmt2@columbia.edu
Rabacchi
S A
SA
Xu
Z
Z
Maroney
A C
AC
Connors
T J
TJ
Shelanski
M L
ML
Greene
L A
LA
D000544:Alzheimer Disease / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology; D053143:Caspase 2; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D051381:Rats; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014162:Transfection
D016229:Amyloid beta-Peptides; D002227:Carbazoles; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases