Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by beta-amyloid peptide.
The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. beta-amyloid peptide (A beta) accumulation contributes to neurodegeneration in AD, but mechanisms underlying A beta toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both A beta-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.
Lebeau
A
A
Unité 339 INSERM-UPMC, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
Terro
F
F
Rostene
W
W
Pelaprat
D
D
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002478:Cells, Cultured; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats
D016229:Amyloid beta-Peptides; D016859:Lipoxygenase Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D016755:Proto-Oncogene Proteins c-jun; D001092:Arachidonate 12-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase