Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Abstract

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. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-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.

Baicalein and 12/15-Lipoxygenase in the Ischemic Brain

“…This increase is detected predominantly in neurons, consistent with previous studies showing 12/15-LOX involvement in neuronal cell death in vitro. 11,[25][26][27][28] In addition, we also found increased levels of 12/15-LOX in endothelial cells in some cases, the significance of which we are currently investigating (data not shown). The strongest increases in 12/15-LOX expression were thus detected in neurons and sometimes endothelial cells, but 12/15-LOX in other cell types of the brain 29 -31 may also contribute to the effects on stroke pathophysiology shown here.…”

Arachidonate 12/15-Lipoxygenase–Induced Inflammation and Oxidative Stress Are Involved in the Development of Diabetic Cardiomyopathy

“…Furthermore, the role of 12/15-LOX has been suggested in humans as well. Indeed, the expression of 12/15-LOX was shown to be an independent risk factor for atherosclerosis in 828 patients with diabetes (42), and 12/15-LOX inhibition is shown to lead to reductions in the size of cerebral infarction in humans (43)(44)(45)(46).…”

Absence of 12/15 Lipoxygenase Reduces Brain Oxidative Stress in Apolipoprotein E-Deficient Mice

“…25 However, despite some circumstantial evidence suggesting that this enzyme may also play a role in neurodegeneration and in the apoptotic responses of cortical neurons, a definite biological role for 12/15LO in the CNS has yet to be established. 26,27 Previous studies have shown that when LDL is incubated with 12/15LO-transfected fibroblasts they become seeded with hydroperoxides and develop biological Results are mean Ϯ SEM.…”