Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment

doi:10.1016/j.neulet.2005.12.017

Neuroscience Letters

Volume 397, Issue 3, 24 April 2006, Pages 170-173

https://doi.org/10.1016/j.neulet.2005.12.017 Get rights and content

Abstract

Oxidative damage is a feature of many age-related neurodegenerative diseases, including Alzheimer's disease (AD). 4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the free radical-mediated lipid peroxidation of unsaturated lipids, particularly arachidonic acid, in cellular membranes. In the present study we show for the first time in brain obtained at short postmortem intervals that the levels of HNE are elevated in mild cognitive impairment (MCI) hippocampus and inferior parietal lobules compared to those of control brain. Thus, increased levels of HNE in MCI brain implicate lipid peroxidation as an early event in AD pathophysiology and also suggest that the pharmacologic intervention to prevent lipid peroxidation at the MCI stage or earlier may be a promising therapeutic strategy to delay or prevent progression to AD.

Section snippets

Acknowledgements

The authors would like to thank the University of Kentucky ADRC Clinical Neuropathology Core faculty for providing the brain tissue used for this study. This work was supported in part by NIH grants to D.A.B. [AG-05119; AG-10836].

References (30)

N. Andreasen et al.
Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer's disease in patients with mild cognitive impairment
Neurosci. Lett.
(1999)
D.A. Butterfield et al.
Protein oxidation processes in aging brain
Adv. Cell Aging Gerontol.
(1997)
A. Castegna et al.
Modulation of phospholipid asymmetry in synaptosomal membranes by the lipid peroxidation products, 4-hydroxynonenal and acrolein: implications for Alzheimer's disease
Brain Res.
(2004)
H. Esterbauer et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
(1991)
M.A. Lovell et al.
Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures
Free Radic. Biol. Med.
(2000)
M.A. Lovell et al.
Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures
Neurobiol. Aging
(2001)
W.R. Markesbery et al.
Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer's disease
Neurobiol. Aging
(1998)
H. Mohmmad-Abdul et al.
Protection against amyloid beta-peptide (1-42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: implications for Alzheimer's disease
Biochim. Biophys. Acta
(2005)
A.M. Palmer et al.
Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer's disease
Brain Res.
(1994)
P. Rinaldi et al.
Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease
Neurobiol. Aging
(2003)

N. Andreasen et al.

Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease

Arch. Neurol.

(1999)

L. Balazs et al.

Evidence of an oxidative challenge in the Alzheimer's brain

Neurochem. Res.

(1994)

D.A. Butterfield

Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review

Free Radic. Res.

(2002)

D.A. Butterfield et al.

Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death

Neurobiol. Aging

(2002)

F.W. Holtsberg et al.

Lysophosphatidic acid and apoptosis of nerve growth factor-differentiated PC12 cells

J. Neurosci. Res.

(1998)

Cited by (224)

Low beauvericin concentrations promote PC-12 cell survival under oxidative stress by regulating lipid metabolism and PI3K/AKT/mTOR signaling
2024, Ecotoxicology and Environmental Safety
Beauvericin (BEA), a naturally occurring cyclic peptide with good pharmacological activity, has been widely explored in anticancer research. Although BEA is toxic, studies have demonstrated its antioxidant activity. However, to date, the antioxidant mechanisms of BEA remain unclear. Herein, we conducted a comprehensive and detailed study of the antioxidant mechanism of BEA using an untargeted metabolomics approach, subsequently validating the results. BEA concentrations of 0.5 and 1 μM significantly inhibited H₂O₂-induced oxidative stress (OS), decreased reactive oxygen species levels in PC-12 cells, and restored the mitochondrial membrane potential. Untargeted metabolomics indicated that BEA was primarily involved in lipid-related metabolism, suggesting its role in resisting OS in PC-12 cells by participating in lipid metabolism. BEA combated OS damage by increasing phosphatidylcholine, phosphatidylethanolamine, and sphingolipid levels. In the current study, BEA upregulated proteins related to the PI3K/AKT/mTOR pathway, thereby promoting cell survival. These findings support the antioxidant activity of BEA at low concentrations, warranting further research into its pharmacological effects.
Plasma and cerebrospinal fluid nonenzymatic protein damage is sustained in Alzheimer's disease
2023, Redox Biology
Oxidative stress is considered to play an important role in the pathogenesis of Alzheimer's disease (AD). It has been observed that oxidative damage to specific protein targets affecting particular functional networks is one of the mechanisms by which oxidative stress contributes to neuronal failure and consequently loss of cognition and AD progression. Studies are lacking in which oxidative damage is measured at both systemic and central fluid levels and in the same cohort of patients. We aimed to determine the levels of both plasma and cerebrospinal fluid (CSF) nonenzymatic protein damage in patients in the continuum of AD and to evaluate the relation of this damage with clinical progression from mild cognitive impairment (MCI) to AD.
Different markers of nonenzymatic post-translational protein modification, mostly from oxidative processes, were detected and quantified in plasma and CSF by isotope dilution gas chromatography‒mass spectrometry using selected ion monitoring (SIM-GC/MS) for 289 subjects: 103 AD, 92 MCI, and 94 control subjects. Characteristics of the study population such as age, sex, Mini-mental state examination, CSF AD biomarkers, and APOE ϵ4, were also considered.
Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 ± 12.5 months). After controlling for age, sex, and APOE ϵ4 allele, plasma and CSF concentrations of protein damage markers were not associated with either diagnosis of AD or MCI. The CSF levels of nonenzymatic protein damage markers were associated with none of the CSF AD biomarkers. In addition, neither in CSF nor in plasma were the levels of protein damage associated with the MCI to AD progression.
The lack of association between both CSF and plasma concentrations of nonenzymatic protein damage markers and AD diagnosis and progression suggests that oxidative damage in AD is a pathogenic mechanism specifically expressed at the cell-tissue level, not in extracellular fluids.
NOX4 as a critical effector mediating neuroinflammatory cytokines, myeloperoxidase and osteopontin, specifically in astrocytes in the hippocampus in Parkinson's disease
2023, Redox Biology
Oxidative stress and mitochondrial dysfunction have been believed to play an important role in the pathogenesis of aging and neurodegenerative diseases, including Parkinson's disease (PD). The excess of reactive oxygen species (ROS) increases with age and causes a redox imbalance, which contributes to the neurotoxicity of PD. Accumulating evidence suggests that NADPH oxidase (NOX)-derived ROS, especially NOX4, belong to the NOX family and is one of the major isoforms expressed in the central nervous system (CNS), associated with the progression of PD. We have previously shown that NOX4 activation regulates ferroptosis via astrocytic mitochondrial dysfunction. We have previously shown that activation of NOX4 regulates ferroptosis through mitochondrial dysfunction in astrocytes. However, it remains unclear why an increase in NOX4 in neurodegenerative diseases leads to astrocyte cell death by certain mediators. Therefore, this study was designed to evaluate how NOX4 in the hippocampus is involved in PD by comparing an MPTP-induced PD mouse model compared to human PD patients. We could detect that the hippocampus was dominantly associated with elevated levels of NOX4 and α-synuclein during PD and the neuroinflammatory cytokines, myeloperoxidase (MPO) and osteopontin (OPN), were upregulated particularly in astrocytes. Intriguingly, NOX4 suggested a direct intercorrelation with MPO and OPN in the hippocampus. Upregulation of MPO and OPN induces mitochondrial dysfunction by suppressing five protein complexes in the mitochondrial electron transport system (ETC) and increases the level of 4-HNE leading to ferroptosis in human astrocytes. Overall, our findings indicate that the elevation of NOX4 cooperated with the MPO and OPN inflammatory cytokines through mitochondrial aberration in hippocampal astrocytes during PD.
Fluid redox biomarkers in neurological disease
2023, Modulation of Oxidative Stress: Biochemical, Physiological and Pharmacological Aspects
Redox imbalance is a common physiopathological feature in neurological disease, especially those with a relevant neurodegenerative component. The consequent damage to biomolecules leads to the generation of various relatively stable by-products, which can serve as biomarkers of oxidative stress. A wealth of epidemiological and clinical evidence has found an association between alteration of these fluid biomarkers and the occurrence of neurological diseases, in particular Alzheimer's disease (AD), vascular dementia (VD), and Parkinson's disease (PD). However, also conflicting results are reported. Herein, we systematically review the published data on this topic highlighting the methodological issues that hinder the definitive appreciation of the use of redox biomarkers in the diagnosis and prediction of the above-mentioned disorders.
Multifaceted role of polyphenols in the treatment and management of neurodegenerative diseases
2022, Chemosphere
Neurodegenerative diseases (NDDs) are conditions that cause neuron structure and/or function to deteriorate over time. Genetic alterations may be responsible for several NDDs. However, a multitude of physiological systems can trigger neurodegeneration. Several NDDs, such as Huntington's, Parkinson's, and Alzheimer's, are assigned to oxidative stress (OS). Low concentrations of reactive oxygen and nitrogen species are crucial for maintaining normal brain activities, as their increasing concentrations can promote neural apoptosis. OS-mediated neurodegeneration has been linked to several factors, including notable dysfunction of mitochondria, excitotoxicity, and Ca²⁺ stress. However, synthetic drugs are commonly utilized to treat most NDDs, and these treatments have been known to have side effects during treatment. According to providing empirical evidence, studies have discovered many occurring natural components in plants used to treat NDDs. Polyphenols are often safer and have lesser side effects. As, epigallocatechin-3-gallate, resveratrol, curcumin, quercetin, celastrol, berberine, genistein, and luteolin have p-values less than 0.05, so they are typically considered to be statistically significant. These polyphenols could be a choice of interest as therapeutics for NDDs. This review highlighted to discusses the putative effectiveness of polyphenols against the most prevalent NDDs.
mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder
2021, Free Radical Biology and Medicine
Citation Excerpt :
In turn, protein modification can take place as a result of indirect oxidation by formation of protein adducts with 4-HNE. Increased levels of 4-HNE were reported in brain regions showing histopathological alterations of AD in this disorder and its earlier stage, MCI [31–36]. Oxidative modification of lipoic acid by 4-HNE was altered in AD hippocampus, with implications for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase enzymatic activities [37].
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD.
To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.

View all citing articles on Scopus

View full text

Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Adv. Cell Aging Gerontol.

Brain Res.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Neurobiol. Aging

Neurobiol. Aging

Biochim. Biophys. Acta

Brain Res.

Neurobiol. Aging

Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease

Arch. Neurol.

Evidence of an oxidative challenge in the Alzheimer's brain

Neurochem. Res.

Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review

Free Radic. Res.

Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death

Neurobiol. Aging

Lysophosphatidic acid and apoptosis of nerve growth factor-differentiated PC12 cells

J. Neurosci. Res.