Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment
ABSTRACT The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls. Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD. Compared with controls, there was a significant increase of both metabolites in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD.
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ABSTRACT: 12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans.Journal of Neurochemistry 11/2007; 103(1):380-7. DOI:10.1111/j.1471-4159.2007.04742.x · 4.24 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a chronic neurodegenerative condition characterized by progressive memory loss. Mutations in genes involved in the production of amyloid-β (Aβ) are linked to the early-onset variant of AD. However, the most common form, sporadic AD, is considered to be the result of an interaction between environmental risk factors and various genes. Among them, recent work has highlighted the potential role that the 12/15-lipoxygenase (12/15LO) pathway may play in AD pathogenesis. 12/15LO is widely distributed in the central nervous system, and its levels are upregulated in patients with AD or mild cognitive impairments. Studies using animal models have implicated 12/15LO in the molecular pathology of AD, including the metabolism of Aβ and tau, synaptic integrity, and cognitive functions. We provide an overview of this pathway and its relevance to AD pathogenesis, discuss the mechanism(s) involved, and provide an assessment of how targeting 12/15LO could lead to novel AD therapeutics. Copyright © 2015 Elsevier Ltd. All rights reserved.Trends in Pharmacological Sciences 02/2015; DOI:10.1016/j.tips.2015.01.005 · 9.99 Impact Factor
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ABSTRACT: The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitor in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficit and biochemical abnormalities in rats. ICV-STZ is a widely used model of sporadic Alzheimer's disease. In this study, STZ was administered intracerebroventricular (ICV)-bilaterally 3 mg/kg in rats. The STZ-injected rats were treated with different doses of licofelone (2.5, 5, and 10 mg/kg, p.o.) for 21 days. Cognitive functions were assessed by using Morris water maze and passive avoidance task. Levels of malondialdehyde (MDA), nitrite, reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were determined to check oxidative stress and cholinergic function. Cytokine levels (IL-1β and TNF-α) were also determined as markers of neuroinflammation. Administration of STZ caused a significant increase in AChE activity and cognitive dysfunction. Increased oxidative stress and the proinflammatory cytokine levels were also observed following STZ administration in rats. Licofelone treatment attenuated STZ-induced cholinergic hypofunction and cognitive deficit in rats. In addition, licofelone attenuated STZ-induced oxidative stress and elevated cytokine levels. The cognitive enhancement following licofelone administration in STZ rats may be due to its ability to restore cholinergic functions or its antioxidant activity. These observed results suggest the therapeutic potential of dual COX/5-LOX inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment.Journal of Molecular Neuroscience 09/2014; 55(3). DOI:10.1007/s12031-014-0414-4 · 2.76 Impact Factor