The switch of tau protein to an Alzheimer‐like state includes the phosphorylation of two serine‐proline motifs upstream of the microtubule binding region.
Open accessAbstract
The paired helical filaments (PHFs) of Alzheimer's disease consist mainly of the microtubule-associated protein tau. PHF tau differs from normal human brain tau in that it has a higher Mr and a special state of phosphorylation. However, the protein kinase(s) involved, the phosphorylation sites on tau and the resulting conformational changes are only poorly understood. Here we show that a new monoclonal antibody, AT8, records the PHF-like state of tau in vitro, and we describe a kinase activity that turns normal tau into a PHF-like state. The epitope of AT8 is around residue 200, outside the region of internal repeats and requires the phosphorylation of serines 199 and/or 202. Both of these are followed by a proline, suggesting that the kinase activity belongs to the family of proline-directed kinases. The epitope of AT8 is nearly coincident with that of another phosphorylation-dependent antibody, TAU1 [Binder, L.I., Frankfurter, A. and Rebhun, L. (1985) J. Cell Biol., 101, 1371-1378], but the two are complementary since TAU1 requires a dephosphorylated epitope.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tau phosphorylation at S202/T205 as detected by the AT8 antibody is commonly found in tauopathies.
“Tau phosphorylation at S202/T205 as detected by the AT8 antibody (80) is commonly found in tauopathies (38,81–84).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [80]
The indexed Abstract identifies AT8 as a phosphorylation-dependent antibody whose epitope is around residue 200, supporting the AT8 identification cited as (80). It specifies phosphorylation of serines 199 and/or 202, however, not T205. The separate claim that this phosphorylation is common in tauopathies is attached to other citations, not (80). (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 21
- Binder L. I., Frankfurter A., Rebhun L. I. The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985 Oct;101(4):1371–1378. doi: 10.1083/jcb.101.4.1371. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Brion J. P., Hanger D. P., Bruce M. T., Couck A. M., Flament-Durand J., Anderton B. H. Tau in Alzheimer neurofibrillary tangles. N- and C-terminal regions are differentially associated with paired helical filaments and the location of a putative abnormal phosphorylation site. Biochem J. 1991 Jan 1;273(Pt 1):127–133. doi: 10.1042/bj2730127. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Flament S., Delacourte A. Abnormal tau species are produced during Alzheimer's disease neurodegenerating process. FEBS Lett. 1989 Apr 24;247(2):213–216. doi: 10.1016/0014-5793(89)81337-7. [DOI] [PubMed] [Google Scholar] · DOI
- Geisler N., Vandekerckhove J., Weber K. Location and sequence characterization of the major phosphorylation sites of the high molecular mass neurofilament proteins M and H. FEBS Lett. 1987 Sep 14;221(2):403–407. doi: 10.1016/0014-5793(87)80964-x. [DOI] [PubMed] [Google Scholar] · DOI
- Goedert M., Spillantini M. G., Jakes R. Localization of the Alz-50 epitope in recombinant human microtubule-associated protein tau. Neurosci Lett. 1991 May 27;126(2):149–154. doi: 10.1016/0304-3940(91)90541-z. [DOI] [PubMed] [Google Scholar] · DOI
- Goedert M., Spillantini M. G., Jakes R., Rutherford D., Crowther R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989 Oct;3(4):519–526. doi: 10.1016/0896-6273(89)90210-9. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Goedert M., Wischik C. M., Crowther R. A., Walker J. E., Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051–4055. doi: 10.1073/pnas.85.11.4051. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Greenberg S. G., Davies P. A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5827–5831. doi: 10.1073/pnas.87.15.5827. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- Hagestedt T., Lichtenberg B., Wille H., Mandelkow E. M., Mandelkow E. Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. J Cell Biol. 1989 Oct;109(4 Pt 1):1643–1651. doi: 10.1083/jcb.109.4.1643. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Himmler A., Drechsel D., Kirschner M. W., Martin D. W., Jr Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol. 1989 Apr;9(4):1381–1388. doi: 10.1128/mcb.9.4.1381-1388.1989. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Ishiguro K., Omori A., Sato K., Tomizawa K., Imahori K., Uchida T. A serine/threonine proline kinase activity is included in the tau protein kinase fraction forming a paired helical filament epitope. Neurosci Lett. 1991 Jul 22;128(2):195–198. doi: 10.1016/0304-3940(91)90259-v. [DOI] [PubMed] [Google Scholar] · DOI
- Kemp B. E., Pearson R. B. Protein kinase recognition sequence motifs. Trends Biochem Sci. 1990 Sep;15(9):342–346. doi: 10.1016/0968-0004(90)90073-k. [DOI] [PubMed] [Google Scholar] · DOI
- Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M., Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. doi: 10.1016/0896-6273(88)90129-8. [DOI] [PubMed] [Google Scholar] · DOI
- Ksiezak-Reding H., Chien C. H., Lee V. M., Yen S. H. Mapping of the Alz 50 epitope in microtubule-associated proteins tau. J Neurosci Res. 1990 Mar;25(3):412–419. doi: 10.1002/jnr.490250319. [DOI] [PubMed] [Google Scholar] · DOI
- Ksiezak-Reding H., Davies P., Yen S. H. Alz 50, a monoclonal antibody to Alzheimer's disease antigen, cross-reacts with tau proteins from bovine and normal human brain. J Biol Chem. 1988 Jun 15;263(17):7943–7947. [PubMed] [Google Scholar]
- Lee G., Cowan N., Kirschner M. The primary structure and heterogeneity of tau protein from mouse brain. Science. 1988 Jan 15;239(4837):285–288. doi: 10.1126/science.3122323. [DOI] [PubMed] [Google Scholar] · DOI
- Lee V. M., Balin B. J., Otvos L., Jr, Trojanowski J. Q. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991 Feb 8;251(4994):675–678. doi: 10.1126/science.1899488. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- Meyer H. E., Hoffmann-Posorske E., Heilmeyer L. M., Jr Determination and location of phosphoserine in proteins and peptides by conversion to S-ethylcysteine. Methods Enzymol. 1991;201:169–185. doi: 10.1016/0076-6879(91)01016-u. [DOI] [PubMed] [Google Scholar] · DOI
- Steiner B., Mandelkow E. M., Biernat J., Gustke N., Meyer H. E., Schmidt B., Mieskes G., Söling H. D., Drechsel D., Kirschner M. W. Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J. 1990 Nov;9(11):3539–3544. doi: 10.1002/j.1460-2075.1990.tb07563.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- Studier F. W., Rosenberg A. H., Dunn J. J., Dubendorff J. W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol. 1990;185:60–89. doi: 10.1016/0076-6879(90)85008-c. [DOI] [PubMed] [Google Scholar] · DOI
Cited by
Sorted by citations
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · see citing works
“To determine whether our 5XFAD mice exhibited abnormal tau phosphorylation similar to that observed in neurofibrillary tangles, we immunostained sections of Tg6799 brain from aged mice with antibody AT8 (Biernat et al., 1992).”
ResultBraak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., & Del Tredici, K. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0127-z · Cited by 3,172 · see citing works
Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.-H., Mistl, C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., Paganetti, P. A., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.13287 · Cited by 1,507 · see citing works
von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E.-M., & Mandelkow, E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5129 · Cited by 1,021 · see citing works
Self-citationAugustinack, J. C., Schneider, A., Mandelkow, E.-M., & Hyman, B. T. (2002) · Acta Neuropathologica · doi:10.1007/s004010100423 · Cited by 998 · see citing works
Self-citationMorris, M., Maeda, S., Vossel, K., & Mucke, L. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.009 · Cited by 899 · see citing works
Alonso, A. D. C., Grundke-Iqbal, I., & Iqbal, K. (1996) · Nature Medicine · doi:10.1038/nm0796-783 · Cited by 859 · see citing works
Köpke, E., Tung, Y. C., Shaikh, S., Alonso, A. C., Iqbal, K., & Grundke-Iqbal, I. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80536-5 · Cited by 779 · see citing works
Proteopathic tau seeding predicts tauopathy in vivo
Holmes, B. B., Furman, J. L., Mahan, T. E., Yamasaki, T. R., Mirbaha, H., Eades, W. C., Belaygorod, L., Cairns, N. J., Holtzman, D. M., & Diamond, M. I. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411649111 · Cited by 696 · see citing works
Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205
Goedert, M., Jakes, R., & Vanmechelen, E. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11484-e · Cited by 608 · see citing works
Self-citationKampers, T., Friedhoff, P., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01386-5 · Cited by 548 · see citing works
Self-citationStrittmatter, W. J., Saunders, A. M., Goedert, M., Weisgraber, K. H., Dong, L. M., Jakes, R., Huang, D. Y., Pericak-Vance, M., Schmechel, D., & Roses, A. D. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.11183 · Cited by 474 · see citing works
Self-citationLiquid-liquid phase separation induces pathogenic tau conformations in vitro
Kanaan, N. M., Hamel, C., Grabinski, T., & Combs, B. (2020) · Nature Communications · doi:10.1038/s41467-020-16580-3 · Cited by 397 · see citing works
Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments
Barghorn, S., & Mandelkow, E. (2002) · Biochemistry · doi:10.1021/bi026469j · Cited by 341 · see citing works
Self-citationAnalysis of microtubule-associated protein tau glycation in paired helical filaments.
Ledesma, M. D., Bonay, P., Colaço, C., & Avila, J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31849-5 · Cited by 333 · see citing works
Demars, M., Hu, Y., Gadadhar, A., & Lazarov, O. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22387 · Cited by 326 · see citing works
Paudel, H. K., Lew, J., Ali, Z., & Wang, J. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49492-1 · Cited by 285 · see citing works
Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B
Wang, J.-Z., Gong, C.-X., Zaidi, T., Grundke-Iqbal, I., & Iqbal, K. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.9.4854 · Cited by 269 · see citing works
Huang, Y., Weisgraber, K. H., Mucke, L., & Mahley, R. W. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:189 · Cited by 242 · see citing works
Interplay of pathogenic forms of human tau with different autophagic pathways
Caballero, B., Wang, Y., Diaz, A., Tasset, I., Juste, Y. R., Stiller, B., Mandelkow, E., Mandelkow, E., & Cuervo, A. M. (2018) · Aging Cell · doi:10.1111/acel.12692 · Cited by 213 · see citing works
Self-citationTau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo
Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L., & Feany, M. B. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-04-0327 · Cited by 187 · see citing works
Nisbet, R. M., Van der Jeugd, A., Leinenga, G., Evans, H. T., Janowicz, P. W., & Götz, J. (2017) · Brain · doi:10.1093/brain/awx052 · Cited by 187 · see citing works
Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
Huang, Y. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.04.004 · Cited by 170 · see citing works
Karsten, S. L., Sang, T.-K., Gehman, L. T., Chatterjee, S., Liu, J., Lawless, G. M., Sengupta, S., Berry, R. W., Pomakian, J., Oh, H. S., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.019 · Cited by 147 · see citing works
Kanai, Y., & Hirokawa, N. (1995) · Neuron · doi:10.1016/0896-6273(95)90298-8 · Cited by 144 · see citing works
Avila, J., Jiménez, J. S., Sayas, C. L., Bolós, M., Zabala, J. C., Rivas, G., & Hernández, F. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00262 · Cited by 140 · see citing works
Ferreira, A., & Bigio, E. H. (2011) · Molecular Medicine · doi:10.2119/molmed.2010.00220 · Cited by 112 · see citing works
Ambegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
“Tau phosphorylation at S202/T205 as detected by the AT8 antibody (80) is commonly found in tauopathies (38,81–84).”
BackgroundFerreira, A., Kincaid, R., & Kosik, K. S. (1993) · Molecular Biology of the Cell · doi:10.1091/mbc.4.12.1225 · Cited by 110 · see citing works
Leroy, K., Ando, K., Héraud, C., Yilmaz, Z., Authelet, M., Boeynaems, J.-M., Buée, L., De Decker, R., & Brion, J.-P. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1276 · Cited by 103 · see citing works
Boche, D., Donald, J., Love, S., Harris, S., Neal, J. W., Holmes, C., & Nicoll, J. A. R. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0705-y · Cited by 85 · see citing works
Interleukin-10 deficiency exacerbates inflammation-induced tau pathology
Weston, L. L., Jiang, S., Chisholm, D., Jantzie, L. L., & Bhaskar, K. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02211-1 · Cited by 69 · see citing works
Losev, Y., Frenkel-Pinter, M., Abu-Hussien, M., Viswanathan, G. K., Elyashiv-Revivo, D., Geries, R., Khalaila, I., Gazit, E., & Segal, D. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03643-3 · Cited by 52 · see citing works
Losev, Y., Paul, A., Frenkel-Pinter, M., Abu-Hussein, M., Khalaila, I., Gazit, E., & Segal, D. (2019) · Scientific Reports · doi:10.1038/s41598-019-39218-x · Cited by 50 · see citing works
Latimer, D. A., Gallo, J.-M., Lovestone, S., Miller, C. C. J., Hugh Reynolds, C., Marquardt, B., Stabel, S., Woodgett, J. R., & Anderton, B. H. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00434-b · Cited by 48 · see citing works
Spontaneous pathology in PS19 tauopathy mice progresses via brain networks
Ramirez, D. M. O., Whitesell, J. D., Bhagwat, N., Thomas, T. L., Ajay, A. D., Nawaby, A., Delatour, B., Bay, S., LaFaye, P., Harris, J. A., et al. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107072 · Cited by 5 · see citing works
- Authors
- Biernat, J., Mandelkow, E. M., Schröter, C., Lichtenberg‐Kraag, B., Steiner, B., Berling, B., Meyer, H., Mercken, M., Vandermeeren, A., & Goedert, M.
- Affiliations
- Max Planck Unit for Structural Molecular Biology (DE)
- Venue
- The EMBO Journal
- Published
- 1992-04-01
- Volume
- 11
- Issue
- 4
- Pages
- 1593-1597
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC556608
- OpenAlex
- W126426573
- Cited by
- 484
- References
- 0
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 5 · 2023: 15 · 2022: 9 · 2021: 11 · 2020: 16 · 2019: 10 · 2018: 4 · 2017: 11 · 2016: 15 · 2015: 10 · 2014: 7 · 2013: 6 · 2012: 11
- FWCI
- 28.35
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DESY (CERN, DESY, Fermilab, IHEP, and SLAC) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Physiology › 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, paired helical filaments, tau phosphorylation, proline-directed kinases, microtubule-binding region, conformational change
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Animals, Binding Sites, Brain, Cattle, Cloning, Molecular, Humans, Microtubules, Molecular Sequence Data, Peptide Fragments, Phosphopeptides, Phosphorylation, Plasmids, Proline, Protein Kinases, Serine, Swine, tau Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
