Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide
Abstract
Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.
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Aβ plaques facilitate a positive feedback loop of increasing oxidative stress and elevated Aβ levels, leading to neuritic dystrophy and neuronal death.
“Aβ plaques also play a role in facilitating a positive feedback loop of increasing oxidative stress and subsequently elevated Aβ levels, leading to neuritic dystrophy and culminating in neuronal death [16,17,18,19].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [18]
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References 34 · Cited by 406
- Authors
- Yan, S. D., Yan, S. F., Chen, X., Fu, J., Chen, M., Kuppusamy, P., Smith, M. A., Perry, G., Godman, G. C., Nawroth, P., Zweier, J. L., & Stern, D.
- Affiliations
- Columbia University (US)
- Johns Hopkins University (US)
- Case Western Reserve University (US)
- Heidelberg University (DE)
- ORCID
- Venue
- Nature Medicine
- Published
- 1995-07
- Volume
- 1
- Issue
- 7
- Pages
- 693-699
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2003742797
- Cited by
- 406
- References
- 34
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 7 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 12 · 2014: 12 · 2013: 8 · 2012: 22
- FWCI
- 14.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hl021006-17, 5r01hl042507-09, 5p50hl017655-17)
- National Heart, Lung, and Blood Institute (HL 42507, HL17655, HL 21006)
- 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
- Alzheimer's disease, glycation, advanced glycation end products, tau protein, neurofibrillary tangles, oxidative stress, oxygen free radicals, NF-κB, cytokine gene expression, amyloid-beta, amyloid precursor protein, tau phosphorylation, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Cerebral Cortex, Cytochrome c Group, Feedback, Gene Expression Regulation, Glycosylation, Humans, Neuroblastoma, Protein Processing, Post-Translational, Superoxide Dismutase, Temporal Lobe, Transfection, Tumor Cells, Cultured, Interleukin-6, Amyloid beta-Protein Precursor, tau Proteins, Reactive Oxygen Species, Oxidative Stress, Rats
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