Effect of Pseudophosphorylation and Cross-linking by Lipid Peroxidation and Advanced Glycation End Product Precursors on Tau Aggregation and Filament Formation
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Accumulation of hyperphosphorylated Tau protein as paired helical filaments in pyramidal neurons is a major hallmark of Alzheimer disease. Besides hyperphosphorylation, other modifications of the Tau protein, such as cross-linking, are likely to contribute to the characteristic features of paired helical filaments, including their insolubility and resistance against proteolytic degradation. In this study, we have investigated whether the four reactive carbonyl compounds acrolein, malondialdehyde, glyoxal, and methylglyoxal accelerate the formation of Tau oligomers, thioflavin T-positive aggregates, and fibrils using wild-type and seven pseudophosphorylated mutant Tau proteins. Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Furthermore, acrolein and methylglyoxal induced the formation of thioflavin T-fluorescent aggregates in a triple pseudophosphorylation-mimicking mutant to a slightly higher degree than wild-type Tau. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde. Our results suggest that reactive carbonyl compounds, particularly methylglyoxal and acrolein, could accelerate tangle formation in vivo and that this process could be slightly accelerated, at least in the case of methylglyoxal and acrolein, by hyperphosphorylation. Interference with the formation or the reaction of these reactive carbonyl compounds could be a promising way of inhibiting tangle formation and neuronal dysfunction in Alzheimer disease and other tauopathies.
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In neuronal tissues, accumulation of AGEs induces glycation of α-synuclein and tau proteins, leading to protein dysfunction and aggregation of harmful protein oligomers capable of initiating and developing neurodegenerative diseases.
“For instance, in neuronal tissues, the accumulation of AGEs induces glycation of α-synuclein and tau proteins, leading to protein dysfunction accompanied by the aggregation of harmful protein oligomers capable of initiating and developing neurodegenerative diseases27,28.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [28]
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- Authors
- Kuhla, B., Haase, C., Flach, K., Lüth, H.-J., Arendt, T., & Münch, G.
- Affiliations
- Research Institute for Farm Animal Biology (FBN) (DE)
- James Cook University (AU)
- Corresponding author
- Kuhla, Björn
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 282
- Issue
- 10
- Pages
- 6984-6991
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2141232168
- Cited by
- 119
- References
- 61
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 11 · 2018: 5 · 2017: 3 · 2016: 11 · 2015: 6 · 2014: 13 · 2013: 7 · 2012: 7
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ResearchOnline at James Cook University (James Cook University) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (01KS9504)
- James Cook University
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, lipid peroxidation, acrolein, methylglyoxal, malondialdehyde, glyoxal, protein cross-linking, tau oligomerization, fibril formation, paired helical filaments, Alzheimer's disease, tauopathy, thioflavin T, hyperphosphorylation
- MeSH terms
- Acrolein, Electrophoresis, Polyacrylamide Gel, Fluorescence, Glyoxal, Humans, Malondialdehyde, Microscopy, Electron, Phosphorylation, Pyruvaldehyde, Blotting, Western, Lipid Peroxidation, Neurofibrillary Tangles, tau Proteins, Glycation End Products, Advanced
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