4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau
Abstract
In Alzheimer's disease (AD) the microtubule-associated protein tau is excessively phosphorylated in degenerating neurons, but the mechanisms underlying the increased phosphorylation are unknown. Recent findings suggest that oxidative stress, and membrane lipid peroxidation in particular, contributes to the neurodegenerative process in AD. We now report that following exposure of cultured rat hippocampal neurons to 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, tau is resistant to dephosphorylation. Immunocytochemical and Western blot analyses using phosphorylation-sensitive tau antibodies showed that HNE treatment causes a moderate increase in basal levels of tau phosphorylation, and prevents tau dephosphorylation by alkaline phosphatase in neurons pretreated with the phosphatase inhibitor okadaic acid. Studies with anti-HNE antibodies showed that HNE binds directly to tau, and that HNE immunoreactivity localizes to cell bodies and axons, cell compartments that contain tau. These data suggest a role for HNE in altered tau phosphorylation and neurofibrillary degeneration in AD.
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4-HNE inhibits dephosphorylation of tau protein.
“It is also known that tau is cleared by proteasomal degradation [54] and that 4-HNE inhibits the dephosphorylation of tau protein [59].”
From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [59]
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- Authors
- Mattson, M. P., Fu, W., Waeg, G., & Uchida, K.
- Affiliations
- University of Kentucky (US)
- University of Graz (AT)
- Venue
- NeuroReport
- Published
- 1997-07
- Volume
- 8
- Issue
- 9
- Pages
- 2275-2281
- ISSN
- 0959-4965 (ISSN-L)
- OpenAlex
- W2088073674
- Cited by
- 176
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2022: 6 · 2021: 3 · 2020: 7 · 2019: 7 · 2018: 1 · 2017: 10 · 2016: 4 · 2013: 2 · 2012: 5
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroreport (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag014554-07, 5r01ns029001-07)
- National Institute on Aging (AG14554)
- National Institute of Neurological Disorders and Stroke (NS29001)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- 4-hydroxynonenal, lipid peroxidation, tau protein, tau phosphorylation, tau dephosphorylation, Alzheimer's disease, oxidative stress, hippocampal neurons, neurofibrillary degeneration, okadaic acid, alkaline phosphatase
- MeSH terms
- Aldehydes, Animals, Cells, Cultured, Hippocampus, Phosphorylation, Blotting, Western, Lipid Peroxidation, Cysteine Proteinase Inhibitors, tau Proteins, Microscopy, Confocal, Okadaic Acid, Rats
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