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Oxidative modification of lipoic acid by HNE in Alzheimer disease brain
Open accessAbstract
Alzheimer disease (AD) is an age-related neurodegenerative disease characterized by the presence of three pathological hallmarks: synapse loss, extracellular senile plaques (SP) and intracellular neurofibrillary tangles (NFTs). The major component of SP is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress. The AD brain shows increased levels of lipid peroxidation products, including 4-hydroxy-2-nonenal (HNE). HNE can react covalently with Cys, His, or Lys residues on proteins, altering structure and function of the latter. In the present study we measured the levels of the HNE-modified lipoic acid in brain of subjects with AD and age-matched controls. Lipoic acid is a key co-factor for a number of proteins including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, key complexes for cellular energetics. We observed a significant decrease in the levels of HNE-lipoic acid in the AD brain compared to that of age-matched controls. To investigate this phenomenon further, the levels and activity of lipoamide dehydrogenase (LADH) were measured in AD and control brains. Additionally, LADH activities were measured after in-vitro HNE-treatment to mice brains. Both LADH levels and activities were found to be significantly reduced in AD brain compared to age-matched control. HNE-treatment also reduced the LADH activity in mice brain. These data are consistent with a two-hit hypothesis of AD: oxidative stress leads to lipid peroxidation that, in turn, causes oxidative dysfunction of key energy-related complexes in mitochondria, triggering neurodegeneration. This study is consonant with the notion that lipoic acid supplementation could be a potential treatment for the observed loss of cellular energetics in AD and potentiate the antioxidant defense system to prevent or delay the oxidative stress in and progression of this devastating dementing disorder.
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“while OH-mediated allylic hydrogen atom abstraction from unsaturated lipid acyl chains initiates the processes of lipid peroxidation, leading to highly reactive nucleophilic unsaturated aldehydes such as 4-hydroxynonenal (HNE) (Figure 2A) [8,13,25,26,27].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [27]
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Modifications of lipoic arm by reactive nitrogen species regulate α-ketoacid dehydrogenasesPreprint
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Metadata
- Authors
- Hardas, S. S., Sultana, R., Clark, A. M., Beckett, T. L., Szweda, L. I., Murphy, M. P., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- Case Western Reserve University (US)
- Corresponding author
- Butterfield, D. Allan
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2013
- Volume
- 1
- Issue
- 1
- Pages
- 80-85
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC3757677
- OpenAlex
- W2039562082
- Cited by
- 120
- References
- 74
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 12 · 2015: 11 · 2014: 18 · 2013: 1
- FWCI
- 9.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- NIH (AG-05119)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- Alzheimer's disease, alpha-lipoic acid, 4-hydroxynonenal, lipid peroxidation, oxidative stress, lipoamide dehydrogenase, protein modification, mitochondrial bioenergetics, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, two-hit hypothesis, neurodegeneration
- MeSH terms
- Aldehydes, Alzheimer Disease, Animals, Brain, Humans, Dihydrolipoamide Dehydrogenase, Thioctic Acid, Male, Mice, Inbred C57BL, Case-Control Studies, Oxidative Stress, Mice
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