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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- "During OXS, it initiates a cascade of cell death by attacking mitochondria and producing destructive reactive oxygen species (Li et al., 2009, 1997; Pallast et al., 2009; Seiler et al., 2008). Evidence suggests that it is also involved in the modulation of tau metabolism (Giannopoulos et al., 2013) and its metabolites have been found in post-mortem brain and cerebral spinal fluid of patients with Alzheimer's disease (Practicò et al., 2004; Yao et al., 2005) and in neurons and endothelial cells surrounding stroke damage (Yigitkanli et al., 2013). The two ALOX12 SNPs implicated in this study are located 4186 base pairs apart on opposite sides of a block of SNPs in high LD spanning the second through eighth exons of the gene. "
ABSTRACT: Oxidative stress has been implicated in many common age-related diseases and is hypothesized to play a role in posttraumatic stress disorder (PTSD)-related neurodegeneration (Miller and Sadeh, 2014). This study examined the influence of the oxidative stress-related genes ALOX 12 and ALOX 15 on the association between PTSD and cortical thickness. Factor analyses were used to identify and compare alternative models of the structure of cortical thickness in a sample of 218 veterans. The best-fitting model was then used for a genetic association analysis in White non-Hispanic participants (n = 146) that examined relationships between 33 single nucleotide polymorphisms (SNPs) spanning the two genes, 8 cortical thickness factors, and each SNP × PTSD interaction. Results identified a novel ALOX12 locus (indicated by two SNPs in perfect linkage disequilibrium: rs1042357 and rs10852889) that moderated the association between PTSD and reduced thickness of the right prefrontal cortex. A whole-cortex vertex-wise analysis showed this effect to be localized to clusters spanning the rostral middle frontal gyrus, superior frontal gyrus, rostral anterior cingulate cortex, and medial orbitofrontal cortex. These findings illustrate a novel factor-analytic approach to neuroimaging-genetic analyses and provide new evidence for the possible involvement of oxidative stress in PTSD-related neurodegeneration. Published by Elsevier Ltd.Psychoneuroendocrinology 09/2015; 62:359-365. DOI:10.1016/j.psyneuen.2015.09.003 · 4.94 Impact Factor
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- "In recent years, our laboratory has been interested in the neurobiology of the 12-15LO, an enzyme with pro-inflammatory activity and widely expressed within the central nervous system (Li et al., 1997; Feinmark et al., 2003; Lebeau et al., 2004; Chinnici et al., 2005). Therefore, 12-15LO enzymatic pathway is up-regulated in AD patients compared to their controls (Pratic o et al., 2004; Yao et al., 2005). Previous findings from our group demonstrate "
ABSTRACT: 12/15-Lipoxygenase (12/15LO) is a lipid-peroxidizing enzyme widely expressed in the central nervous system where it has been involved in the neurobiology of Alzheimer disease (AD) because it modulates Amyloid beta (Aβ) and APP processing. However, its biological effect on tau protein is unknown. We investigated the effect of 12/15LO on tau levels and metabolism in vivo and in vitro and the mechanism involved by using genetic and pharmacologic approaches. While no significant differences were observed in the levels of total tau for both groups, compared with controls, Tg2576 mice over-expressing 12/15LO had elevated levels of phosphorylated tau at two specific epitopes, Ser 202/Thr 205 and Ser 396. In vitro and in vivo studies show that 12/15LO modulates tau metabolism specifically via the cdk5 kinase pathway. Associated with these changes were biochemical markers of synaptic pathology. Finally, 12/15-LO-dependent alteration of tau metabolism was independent from an effect on Aβ. Our findings reveal a novel pathway by which 12/15LO modulates endogenous tau metabolism making this protein an appealing pharmacologic target for treatment of AD and related tauopathies. This article is protected by copyright. All rights reserved.Aging cell 07/2013; 12(6). DOI:10.1111/acel.12136 · 6.34 Impact Factor
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- "Iba-1, a marker for microglia is significantly elevated in AD mice and reduced by J147, while a toxic microglial enzyme, iNOS, is not quite significantly reduced by J147 (Fig. 7B, C). Finally, 5 LOX is a potent reactive oxygen species (ROS) producing and pro-inflammatory enzyme that is increased in AD , . This enzyme is also increased in the transgenic mice but levels are dramatically reduced by J147 (Fig. 7D). "
ABSTRACT: Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.PLoS ONE 12/2011; 6(12):e27865. DOI:10.1371/journal.pone.0027865 · 3.23 Impact Factor