Redox proteomics identification of 4-hydroxynonenal-modified brain proteins in Alzheimer’s disease: Role of lipid peroxidation in Alzheimer’s disease pathogenesis
Open accessAbstract
Numerous studies have shown that neuronal lipids are highly susceptible to oxidative stress including in those brain areas directly involved in the neurodegenerative process of Alzheimer's disease (AD). Lipid peroxidation directly damages membranes and also generates a number of secondary biologically active products (toxic aldehydes)that are capable of easily attacking lipids, proteins, and DNA. Accumulating evidence has demonstrated regionally increased brain lipid peroxidation in patients with AD; however, extensive studies on specific targets of lipid peroxidation-induced damage are still missing. The present study represents a further step in understanding the relationship between oxidative modification of protein and neuronal death associated with AD. We used a proteomics approach to determine specific targets of lipid peroxidation in AD brain, both in hippocampus and inferior parietal lobule, by coupling immunochemical detection of 4-hydroxynonenal-bound proteins with 2-D polyacrylamide gel electrophoresis and MS analysis. We identified 4-hydroxynonenal-bound proteins in the hippocampus and inferior parietal lobule brain regions of subjects with AD. The identified proteins play different biological functions including energy metabolism, antioxidant system, and structural proteins, thus impairing multiple molecular pathways. Our results provide further evidence for the role of lipid peroxidation in the pathogenesis of AD.
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The activities of LDH, aconitase, and ATP synthase are significantly decreased as a result of oxidation.
“The activities of LDH, aconitase, and ATP synthase are significantly decreased as a result of oxidation [54,55,56,61]”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [54]
Results §3.1 reports a 48% decrease in ATP synthase activity in AD brain alongside oxidative modification. Discussion §4.1 reports decreased aconitase activity but says its reduction could result from HNE modification. The paper mentions lactate dehydrogenase (LDH) only as a reagent in the ATP synthase assay (Methods §2.9.1), not as an enzyme whose activity decreased. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGS is oxidatively modified in both MCI and AD brain, likely resulting in the significantly decreased activity observed in AD brain.
“GS is also oxidatively modified in both MCI and AD brain [44,54,59], likely resulting in the significantly decreased activity observed in AD brain [133,134].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [54]
The Results (§3.1) identify HNE-modified glutamine synthase in AD brain, and the Discussion (§4.4) reports decreased glutamine synthase activity in AD and links its loss of activity to oxidative modification. The paper says that some identified proteins were oxidatively modified in MCI brain, but it does not specify glutamine synthase among them; its own samples were from AD subjects and controls (§2.1). (LLM, conf=0.85)
Experimental — accuracy not yet measuredAconitase is significantly modified by HNE in late AD hippocampus and by carbonylation induced by Aβ in vivo.
“Aconitase is an iron–sulfur protein that catalyzes the interconversion of citrate and isocitrate [62] and is a redox-sensitive enzyme that is significantly modified by HNE in late AD hippocampus [54] and by carbonylation induced by Aβ in vivo [63].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [54]
MnSOD is also oxidatively modified by HNE in late AD IPL.
“and is also oxidatively modified by HNE in late AD IPL [54]”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [54]
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References 66 · Cited by 196
Research works printed but not linked: 1
- [58]Anantharaman M Tangpong J Keller JN Murphy MP Beta-amyloid mediated nitraiton of manganese super-oxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease Am. J. Pathol 2006 165 1608 1616 16651627 PMC1606606
- Authors
- Perluigi, M., Sultana, R., Cenini, G., Di Domenico, F., Memo, M., Pierce, W. M., Coccia, R., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- University of Brescia (IT)
- University of Louisville (US)
- Sapienza University of Rome (IT)
- Corresponding author
- Butterfield, D. Allan
- Venue
- PROTEOMICS - CLINICAL APPLICATIONS
- Publisher
- Wiley
- Published
- 2009-06
- Volume
- 3
- Issue
- 6
- Pages
- 682-693
- ISSN
- 1862-8346 (ISSN-L)
- 1862-8354
- PMC
- PMC2843938
- OpenAlex
- W1978287335
- Cited by
- 196
- References
- 66
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 14 · 2020: 11 · 2019: 13 · 2018: 12 · 2017: 9 · 2016: 12 · 2015: 12 · 2014: 11 · 2013: 15 · 2012: 9
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- PROTEOMICS - CLINICAL APPLICATIONS (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- NIH (AG-10836, AG-05119, AG-029839)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Alzheimer's disease, 4-hydroxynonenal, lipid peroxidation, protein oxidative modification, redox proteomics, hippocampus, inferior parietal lobule, neurodegeneration, oxidative stress, lipid peroxidation products, energy metabolism, antioxidant defense
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