4‐Hydroxynonenal‐Derived Advanced Lipid Peroxidation End Products Are Increased in Alzheimer's Disease

Journal of Neurochemistry (Impact Factor: 4.28). 04/1997; 68(5):2092 - 2097. DOI: 10.1046/j.1471-4159.1997.68052092.x


Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine-derived pyrrole adducts formed by lipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age-matched control patients. HNE-pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid-β deposits were unlabeled. Age-matched controls showed only background HNE-pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress-related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.

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Available from: George Perry, Sep 01, 2014
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    • "Its concentration drastically increases during oxidative stress and under pathological conditions such as neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease (Zarkovic, 2003). 4-HNE attains high levels ($20 mM) in brain (Markesbery & Lovell, 1998; Sayre et al., 1997) and plasma (McGrath et al., 2001) of Alzheimer patients compared to aged matched controls, pointing out its involvement in this disease (Poli & Schaur, 2000). Even much higher local concentrations of 4-HNE (50 mM to 5 mM) accumulate in the vicinity of the membrane and membrane bound proteins (Esterbauer et al., 1991; Reed et al., 2008). "
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    ABSTRACT: 4-Hydroxy-2-nonenal (4-HNE) is a reactive aldehyde and a lipid peroxidation product formed in biological tissues under physiological and pathological conditions. Its concentration increases with oxidative stress and induces deleterious modifications of proteins and membranes. Mitochondrial and cytosolic isoforms of creatine kinase were previously shown to be affected by 4-HNE. In the present study, we analyzed the effect of 4-HNE on mitochondrial creatine kinase, an abundant protein from the mitochondrial intermembrane space with a key role in mitochondrial physiology. We show that this effect is double: 4-HNE induces a step-wise loss of creatine kinase activity together with a fast protein aggregation. Protein-membrane interaction is affected and amyloid-like networks formed on the biomimetic membrane. These fibrils may disturb mitochondrial organisation both at the membrane and in the inter membrane space.
    Full-text · Article · Apr 2015 · Molecular Membrane Biology
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    • "These types of adducts, similar to what occur with the introduction of carbonyl groups, cause conformational changes of protein tridimensional structure that in turn affect its function. Protein bound lipid peroxidation products are commonly detected in samples by immunochemical methods or by spectrophotometry [14] [15] [16] [17]. Though lipid hydroperoxides form at membrane level, they are lipophilic and highly reactive and may initiate radical chain reactions on lipids and proteins in an adjacent cellular or organelle membrane [18]. "
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    ABSTRACT: Free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it is a non-reversible phenomenon that requires clearance systems for removal. Major consequences of protein oxidation are loss of protein function and the formation of large protein aggregates, which are often toxic to cells if allowed to accumulate. Deposition of aggregated, misfolded, and oxidized proteins may also result from the impairment of protein quality control (PQC) system, including protein unfolded response, proteasome, and autophagy. Perturbations of such components of the proteostasis network that provides a critical protective role against stress conditions are emerging as relevant factor in triggering neuronal death. In this outlook paper, we discuss the role of protein oxidation as a major contributing factor for the impairment of the PQC regulating protein folding, surveillance, and degradation. Recent studies from our group and from others aim to better understand the link between Down syndrome and Alzheimer's disease neuropathology. We propose oxidative stress and alteration of proteostasis network as a possible unifying mechanism triggering neurodegeneration.
    Full-text · Article · Aug 2014
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    • "Recently, we assessed the level of p62 in the brains of patients with neurodegenerative dementia, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and showed that the level of p62 was significantly increased in the brains of patients with AD relative to controls [9, 10]. Furthermore, consistent with previous reports [11–13], several genes related to the stress response and detoxification were also increased in the brains with AD compared with controls. Interestingly, recent studies have shown that p62 binds directly to Keap1 [14–17], which functions as a stress sensor through regulation of NF-E2 related factor 2 (Nrf2) [18]. "
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    ABSTRACT: Background Extensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget’s disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions. Results To answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer’s disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349. Conclusion These results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD. Electronic supplementary material The online version of this article (doi:10.1186/2051-5960-2-50) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2014
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