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Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease.
Open accessAbstract
The major protein subunit of the paired helical filaments (PHF) of Alzheimer disease (AD) is the microtubule-associated protein tau. Tau is a family of phosphopolypeptides that are abnormally phosphorylated in PHF. In this study, a non-PHF pool of tau abnormally phosphorylated at Ser-199/202, and tau not phosphorylated at this site (AD P-tau and AD tau, respectively) were isolated from the 27,000 x g to 200,000 x g fraction of AD brain homogenate by extraction in 8 M urea, followed by dialysis against Tris buffer. AD P-tau and AD tau were further purified and separated from each other by acid precipitation, glial fibrillary acidic protein affinity chromatography, and phosphocellulose chromatography. The resulting AD P-tau and AD tau preparations were free of cytoskeletal proteins, ubiquitin, and beta-amyloid peptide. Immunochemical and morphological analysis of AD P-tau preparations revealed that most of the protein was of non-PHF origin. The AD P-tau was about 3-4-fold (approximately 8 mol P04/mol protein, M(r) 41,318) more phosphorylated than cytosolic tau from AD and control brains. Unlike PHF, the AD P-tau lacked ubiquitin. In AD brain the levels of cytosolic tau were about half of those in control aged cases. These findings suggest that the abnormal phosphorylation of tau in AD occurs in the cytosol.
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“In the normal adult brain, there are 2–3 mol of phosphate per mole of tau, but in the AD brain, tau protein is twofold to threefold hyperphosphorylated [35].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [35]
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Metadata
- Authors
- Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I.
- Affiliations
- Regeneron (United States) (US)
- ORCID
- Iqbal, K
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1993-11
- Volume
- 268
- Issue
- 32
- Pages
- 24374-24384
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1601433695
- Cited by
- 779
- References
- 52
- Citations by year
- 2026: 22 · 2025: 40 · 2024: 44 · 2023: 42 · 2022: 24 · 2021: 45 · 2020: 49 · 2019: 45 · 2018: 43 · 2017: 29 · 2016: 30 · 2015: 30 · 2014: 29 · 2013: 22 · 2012: 29
- FWCI
- 7.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns018105-17, 5p01ag004220-12)
- National Institute on Aging (F32 AGO 5541, AGO4220)
- National Institute of Neurological Disorders and Stroke (NS 18105)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, Alzheimer's disease, tau phosphorylation, paired helical filaments, ubiquitin
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Chromatography, Affinity, Chromatography, Ion Exchange, Electrophoresis, Polyacrylamide Gel, Humans, Microscopy, Electron, Phosphorylation, Protein Denaturation, Solubility, Ubiquitins, Urea, tau Proteins
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