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  • 1
    Electronic Resource
    Electronic Resource
    Aging, gender and APOE isotype modulate metabolism of Alzheimer's Aβ peptides and F2-isoprostanes in the absence of detectable amyloid deposits (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 90 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aging and apolipoprotein E (APOE) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by-products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid β (Aβ) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOEɛ3 or human APOEɛ4 alleles]. Aging-, gender-, and APOE-genotype-dependent changes were observed for endogenous mouse brain Aβ40 and Aβ42 peptides. Levels of the oxidized lipid F2-isoprostane (F2-isoPs) in the brains of the same animals as those used for the Aβ analyses revealed aging- and gender-dependent changes in APOE KO and in human APOEɛ4 transgenic KO mice. Human APOEɛ3 transgenic KO mice did not exhibit aging- or gender-dependent increases in F2-isoPs. In general, the changes in the levels of brain F2-isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Aβ levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging-dependent, APOE-genotype-sensitive rise in murine brain Aβ levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOEɛ3, but not human APOEɛ4, can apparently prevent the aging-dependent rise in murine brain Aβ levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Aβ/F2-isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F2-isoPs can stimulate Aβ generation and aggregation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02532.x
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 87 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Activation of glial innate immunity is widely proposed to contribute to a number of degenerative and destructive diseases of brain. However, the precise role of activated innate immunity has been difficult to define in vivo because of multiple simultaneous pathogenic processes and responses to injury that confound interpretation of results from complex models of disease. Here, we used the model of intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) to test the hypothesis that directly activated glial innate immunity leads to neurodegeneration in cerebrum and to establish the molecular determinants of and neuroprotectants from such innate immunity-mediated neuronal damage. Our results showed that ICV LPS induced delayed, reversible oxidative damage to cerebral neuronal membranes as measured by F4-neuroprostanes that was coincident with degeneration of the hippocampal pyramidal neuron dendritic system, but not neuron death, in adult mice. Both neuronal oxidative damage and dendritic degeneration were NF-κB and iNOS dependent and were completely suppressed by ibuprofen and α-tocopherol, but not naproxen or γ-tocopherol. These results prove that activation of glial innate immunity can lead to neurodegeneration independent of other pathologic processes, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and provide a possible explanation for the varying efficacy of neuroprotectants that have been suggested in observational studies of dementia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.02120.x
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  • 3
    Electronic Resource
    Electronic Resource
    Prostaglandin H2-derived adducts of proteins correlate with Alzheimer's disease severity (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 94 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The formation of cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive γ-ketoaldehydes, levuglandin (LG) E2 and LGD2. These γ-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03264.x
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  • 4
    Electronic Resource
    Electronic Resource
    4-Hydroxy-trans-2-nonenoic acid is a γ-hydroxybutyrate receptor ligand in the cerebral cortex and hippocampus (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 89 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Elevated production of 4-hydroxy-trans-2-nonenal (HNE) occurs in numerous neurological disorders involving oxidative damage. HNE is metabolized to the non-toxic 4-hydroxy-trans-2-nonenoic acid (HNEAcid) by aldehyde dehydrogenases in the rat cerebral cortex. Based upon the structural similarity of HNEAcid to ligands of the γ-hydroxybutyrate (GHB) receptor, we hypothesized that HNEAcid is an endogenous ligand for the GHB receptor. HNEAcid displaced the specific binding of the GHB receptor ligand 3H-NCS382 (30 nm) in membrane preparations of human frontal cerebral cortex and whole rat cerebral cortex with IC50s of 3.9 ± 1.1 and 5.6 ± 1.2 µm, respectively. Inhibition was attenuated when the carboxyl group of HNEAcid was replaced with an aldehyde or an alcohol. HNEAcid (300 µm) did not displace the binding of β-adrenergic receptor and GABAB receptor antagonists, demonstrating the selectivity of HNEAcid for the GHB receptor. HNEAcid is formed in homogenates of human frontal cortical gray matter in an NAD+-dependent (VMax, 0.71 nmol/min/mg) and NADP+-dependent (VMax, 0.12 nmol/min/mg) manner. Lastly, 3H-NCS382 binding is elevated 2.7-fold with age in the cerebral cortex of rats. Our data demonstrate that an HNE metabolite, formed in rat and human brain, is a signaling molecule analogous to other bioactive lipid peroxidation products.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02442.x
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  • 5
    Electronic Resource
    Electronic Resource
    Role of glutathione in intracellular amyloid-α precursor protein/carboxy-terminal fragment aggregation and associated cytotoxicity (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 93 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Alterations in glutathione (GSH) metabolism are associated with neurodegeneration in Alzheimer's disease (AD), and GSH depletion follows application of exogenous fibrillar amyloid β (Aβ) peptides in experimental systems; these results are commonly cited as evidence of oxidative damage in AD. We used MC65 human neuroblastoma cells that conditionally express carboxy-terminal fragments of the Aβ precursor protein (Aβ/CTFs) to directly test the hypothesis that GSH is part of the cellular response to stressors associated with Aβ/CTF accumulation and not simply a marker of oxidative damage. Our data showed that Aβ/CTFs accumulated by post-translational processes and were associated with progressive increases in oxidative damage and cytotoxicity. Ethycrinic acid (EA) or diethyl maleate (DEM), reagents that deplete GSH through non-specific thiol adduction, gave rise to dose-dependent cytotoxicity that was independent of Aβ/CTF expression and minimally responsive to α-tocopherol (AT). In contrast, buthionine sulfoximine (BSO), a selective inhibitor of GSH synthase, not only augmented Aβ/CTF-associated cell death but unexpectedly potentiated Aβ/CTF accumulation; both outcomes were completely suppressed by AT. These data suggest that antioxidants may serve as ‘Aβ targeting’ therapies that suppress toxic protein aggregation rather than simply acting as downstream radical scavengers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03109.x
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  • 6
    Electronic Resource
    Electronic Resource
    Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 91 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Inheritance of the apolipoprotein (APO) E gene ɛ4 or ɛ2 allele alters the risk of developing Alzheimer disease (AD), while increased alpha-tocopherol (AT) intake appears to lower the risk of AD. As APOE is a major apolipoprotein in the CNS and AT in vivo is transported in lipoproteins, we tested the hypothesis that CNS lipoproteins, as modeled by relevant concentrations of high density lipoprotein (HDL), and AT would interact to suppress neurotoxicity in a cell culture model of amyloid beta (Aβ)- related toxicity. These cells conditionally express C99-derived peptides, proposed to be a key step in AD pathogenesis; this expression is closely associated with subsequent cell death. We found that physiologic concentrations of lipoproteins present in the CNS protected from C99-associated toxicity and provided evidence for two mechanisms of protection. The first was AT-independent, APOE isoform-dependent, and most potent for the APOE2 isoform. The second was a synergistic protection afforded by a combination of APOAI, or less so APOE, and AT. These data provide a novel explanation for the apparent AD-protective effect of inheriting an ɛ2 APOE allele, and suggest that optimizing AT enrichment of CNS lipoproteins or devising APOAI mimetics may augment AT efficacy in treating AD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02818.x
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  • 7
    Electronic Resource
    Electronic Resource
    4-Hydroxy-2(E)-Nonenal Inhibits CNS Mitochondrial Respiration at Multiple Sites (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 72 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: A destructive cycle of oxidative stress and mitochondrial dysfunction is proposed in neurodegenerative disease. Lipid peroxidation, one outcome of oxidative challenge, can lead to the formation of 4-hydroxy-2(E)-nonenal (HNE), a lipophilic alkenal that forms stable adducts on mitochondrial proteins. In this study, we characterized the effects of HNE on brain mitochondrial respiration. We used whole rat brain mitochondria and concentrations of HNE comparable to those measured in patients with Alzheimer’s disease. Our results showed that HNE inhibited respiration at multiple sites. Complex I-linked and complex II-linked state 3 respirations were inhibited by HNE with IC50 values of ∼200 μM HNE. Respiration was apparently diminished owing to the inhibition of complex III activity. In addition, complex II activity was reduced slightly. The lipophilicity and adduction characteristics of HNE were responsible for the effects of HNE on respiration. The inhibition of respiration was not prevented by N-acetylcysteine or aminoguanidine. Studies using mitochondria isolated from porcine cerebral cortex also demonstrated an inhibition of complex I- and complex II-linked respiration. Thus, in neurodegenerative disease, oxidative stress may impair mitochondrial respiration through the production of HNE.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.721617.x
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  • 8
    Electronic Resource
    Electronic Resource
    Enhancement of Dopaminergic Neurotoxicity by the Mercapturate of Dopamine (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The mechanisms that underlie dopaminergic neurodegeneration in Parkinson's disease (PD) are not known but have been proposed to involve oxidation of dopamine and related catechols. In other organ systems, cytotoxicity from catechol oxidation is profoundly influenced by mercapturate metabolism. Here we have tested the hypothesis that catechol thioethers produced in the mercapturic acid pathway may act as dopaminergic neurotoxins. A rat mesencephalic/neuroblastoma hybrid (MES) cell line was exposed to dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), or eight different catechol thioethers for up to 24 h, and the extent of apoptosis was quantified by a microculture kinetic assay. Apoptosis also was confirmed morphologically with Giemsa-stained cultures and by demonstration of internucleosomal DNA fragmentation. The results showed that dopamine at 5-50 μM produced concentration-dependent increases in the percentage of apoptotic MES cells. At 25 and 50 μM dopamine, the maximal proportions of apoptotic cells were detected at ∼ 19 (20.7 ± 2.0%) and 14 h (30.3 ± 3.5%), respectively. None of the catechol thioethers (up to 5 μM) alone induced significant apoptosis in MES cells. However, when MES cells were incubated with dopamine (25 μM) and catechol thioethers (5 μM) to mimic pathological conditions, 5-S-N-acetylcysteinyldopamine, 5-S-homocysteinyldopamine, and 5-S-homocysteinyl-DOPAC significantly increased the percentage of apoptotic cells compared with dopamine alone. These results suggest that mercapturate metabolism of endogenous catechols may yield products that facilitate dopaminergic neurodegeneration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0740970.x
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  • 9
    Electronic Resource
    Electronic Resource
    Prostaglandin H2 (PGH2) accelerates formation of amyloid β1−42 oligomers (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 82 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Epidemiologic evidence implicates cyclooxygenase activity in the pathogenesis of Alzheimer's disease, in which amyloid plaques have been found to contain increased levels of dimers and higher multimers of the amyloid β peptide. The product of the oxygenation of arachidonic acid by the cyclooxygenases, prostaglandin H2 (PGH2), rearranges non-enzymatically to several prostaglandins, including the highly reactive γ-keto aldehydes, levuglandins E2 and D2. We demonstrate that PGH2 markedly accelerates the formation of dimers and higher oligomers of amyloid β1−42. This is associated with the formation of levuglandin adducts of the peptide. These findings provide the molecular basis for a hypothesis linking cyclooxygenase activity to the formation of oligomers of amyloid β.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01064.x
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  • 10
    Electronic Resource
    Electronic Resource
    Cysteine and mercapturate conjugates of oxidized dopamine are in human striatum but only the cysteine conjugate impedes dopamine trafficking in vitro and in vivo (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recent results have suggested that some products of mercapturic acid pathway (MAP) metabolism of oxidized dopamine (DA) may contribute to mesostriatal dopaminergic neurodegeneration, and that at least one product, 5-S-cysteinyldopamine (Cys-DA), is elevated in patients with advanced Parkinson's disease (PD) who have been treated with l-DOPA. Here we investigated MAP enzymes and products in the midbrain and striatum of control individuals and patients with dementia with Lewy bodies (DLB) who had less severe dopaminergic degeneration than PD patients and who were not treated with l-DOPA. We also determined the biological activity of MAP metabolites of oxidized DA using primary rat mesencephalic cultures, rat cerebral synaptosomes, and rat striatum in vivo microdialysis. Our results showed that the human mesostriatal dopaminergic pathway generates Cys-DA but has limited enzymatic capacity for mercapturate formation, that striatal levels of MAP products of oxidized DA are not elevated in DLB patients compared with controls, and that Cys-DA interferes with trafficking of DA in vitro and in vivo. These results indicate that while Cys-DA is not increased in striatum of patients with mild dopaminergic neurodegeneration, it may interfere with uptake of DA in patients with advanced PD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00586.x
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