Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer’s disease
Abstract
In the last decade an important role for the progression of neuronal cell death in Alzheimer's disease (AD) has been ascribed to oxidative stress. trans-4-Hydroxy-2-nonenal, a product of lipid peroxidation, forms conjugates with a variety of nucleophilic groups such as thiols or amino moieties. Here we report for the first time the quantitation of glutathione conjugates of trans-4-hydroxy-2-nonenal (HNEGSH) in the human postmortem brain using the specific and very sensitive method of electrospray ionization triple quadrupole mass spectrometry (ESI-MS-MS). Levels of HNEGSH conjugates calculated as the sum of three chromatographically separated diastereomers were determined in hippocampus, entorhinal cortex, substantia innominata, frontal and temporal cortex, as well as cerebellum from patients with AD and controls matched for age, gender, postmortem delay and storage time. Neither age, nor postmortem delay, nor storage time did correlate with levels of HNEGSH conjugates which ranged between 1 and 500 pmol/g fresh weight in the brain areas examined. The brain specimen from patients with clinically and neuropathologically probable AD diagnosed according to criteria of the consortium to establish a registry for AD (CERAD) show increased levels of HNEGSH in the temporal and frontal cortex, as well as in the substantia innominata. Classification of disease severity according to Braak and Braak, which takes into consideration the amount of neurofibrillary tangles and neuritic plaques, revealed highest levels of HNEGSH in the substantia innominata and the hippocampus, two brain regions known to be preferentially affected in AD. These results substantiate the link between conjugates of glutathione with a product of lipid peroxidation and Alzheimer's disease and justify further studies to evaluate the role of HNE metabolites as potential biomarkers for disease progression in AD.
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GCLC is the main regulating protein for glutathione production, a process impacted by AD pathology.
“GCLC is the main regulating protein for glutathione production, a process impacted by AD pathology [24,25,26].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [25]
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- Authors
- Völkel, W., Sicilia, T., Pähler, A., Gsell, W., Tatschner, T., Jellinger, K., Leblhuber, F., Riederer, P., Lutz, W. K., & Götz, M. E.
- Affiliations
- University of Würzburg (DE)
- F. Hoffmann-La Roche AG (CH)
- Gespag (AT)
- Corresponding author
- Götz, Mario E.
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 48
- Issue
- 8
- Pages
- 679-686
- ISSN
- 0197-0186 (ISSN-L)
- OpenAlex
- W2093441949
- Cited by
- 76
- References
- 68
- Citations by year
- 2026: 1 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 7 · 2012: 4
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- OpenAgrar (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, 4-hydroxynonenal, glutathione conjugates, lipid peroxidation, oxidative stress, brain, postmortem brain, hippocampus, substantia innominata, disease severity, biomarkers, neurofibrillary tangles, neuritic plaques, Braak staging
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Aldehydes, Alzheimer Disease, Brain, Female, Glutathione, Hippocampus, Humans, Male, Nerve Degeneration, Neurons, Mass Spectrometry, Substantia Innominata, Substantia Nigra, Lipid Peroxidation, Up-Regulation, Neurofibrillary Tangles, Oxidative Stress, Plaque, Amyloid
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