Cited by 929Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsNeuroinflammation and Neurodegeneration Mechanisms

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Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.

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Goedert, M., Jakes, R.·1990·The EMBO Journal

DOI 10.1002/j.1460-2075.1990.tb07870.xPMC PMC552204

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Abstract

We have expressed six previously cloned isoforms of human microtubule-associated tau protein in Escherichia coli and purified them to homogeneity in a biologically active form. They range from 352 to 441 amino acids in length and differ from each other by the presence of three or four tandem repeats in the carboxy-terminal half and by the presence or absence of 29 or 58 amino acid inserts in the amino-terminus. When mixed together they gave a set of six bands on SDS-PAGE gels with apparent molecular weights of 48-67 kd and with a characteristic pattern of spacings. Four of these bands aligned with the major tau bands found in adult human cerebral cortex following perchloric acid extraction and alkaline phosphatase treatment. They consisted of isoforms with three repeats and no insertions, four repeats and no amino-terminal insertions and three- and four-repeat containing isoforms with the 29 amino acid insertion. In fetal human brain extracts treated with alkaline phosphatase one of the two major tau bands aligned with the three-repeat containing isoform with no insertions, whereas the molecular nature of the second major tau band remains to be established. The recombinant tau isoforms were biologically active at micromolar concentrations, as assessed by their ability to promote microtubule assembly. The rates of assembly were 2.5-3.0 times faster for isoforms containing four repeats when compared with three-repeat containing isoforms, with no significant contribution by the amino-terminal insertions.

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Umeda, H., Sawazaki, T., Furuta, M., Suzuki, T., Kawashima, S. A., Mitsunuma, H., Hori, Y., Tomita, T., Sohma, Y., & Kanai, M. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00264 · Cited by 10
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Haut, F., Argyrousi, E. K., & Arancio, O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010259 · Cited by 11
“Although different isoforms are expressed in different developmental stages, the adult brain expresses all six Tau isoforms with equal amounts of 3R and 4R isoforms, but unequal amounts of 1N, 0N, and 2N [112,113].”
Background
Impaired APP activity and altered tau splicing in embryonic stem cell-derived astrocytes derived from the APPsw transgenic minipig
Hall, V. J., Lindblad, M. M., Jakobsen, J. E., Gunnarsson, A., Schmidt, M. H., Rasmussen, M. A., Volke, D., Züchner, T., & Hyttel, P. (2015) · Disease Models & Mechanisms · doi:10.1242/dmm.019489 · Cited by 10
“The recombinant human tau isoforms have molecular weights of 48-67 kDa, with 3R,0N migrating at 48 kDa, 4R,0N at 52 kDa, 3R,29N at 54 kDa, 4R,29N at 59 kDa, 3R,58N at 62 kDa and 4R,58N at 67 kDa (Goedert and Jakes, 1990).”
Saccharomyces cerevisiae as a research tool for RNA ‐mediated human disease
Gastelum, S., Michael, A. F., & Bolger, T. A. (2023) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1814 · Cited by 11
“Alternative splicing leads to six tau isoforms, and some isoforms, containing a higher number of tubulin-binding repeat regions, bind with greater affinity to microtubules (Goedert & Jakes, 1990).”
Background
Simultaneous Detection of Six Isoforms of Tau Protein in Human Cerebrospinal Fluid by Multidimensional Mass Spectrometry-Based Targeted Proteomics
Xu, M., Lu, M., Zhang, W., Jin, Q., & Chen, Y. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.0c00826 · Cited by 12
Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells
Ebneth, A., Drewes, G., Mandelkow, E., & Mandelkow, E. (1999) · Cell Motility and the Cytoskeleton · doi:10.1002/(sici)1097-0169(199911)44:3 · Cited by 159
Insights from Drosophila on Aβ- and tau-induced mitochondrial dysfunction: mechanisms and tools
Varte, V., Munkelwitz, J. W., & Rincón-Limas, D. E. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1184080 · Cited by 9
“The ratio of 3R to 4R is 1 in the healthy human brain (Kosik et al., 1989; Goedert and Jakes, 1990), but this ratio is altered in tauopathies (D’Souza and Schellenberg, 2005; Goedert and Jakes, 2005; Sergeant et al.”
Background
Diagnostic and therapeutic targeting of pathological tau proteins in neurodegenerative disorders
Sahara, N., & Higuchi, M. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13711 · Cited by 9
“In the adult human brain, similar levels of 3R and 4R tau isoforms are expressed [19].”
Background
Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein
Liang, J., Li, R., Wong, G., & Huang, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00879-0 · Cited by 13
“The exclusion of exon 10 results in the production of 3R-Tau, which contains three microtubule-binding domain (MTBD) repeats, whereas the inclusion of exon 10 leads to the production of 4R-Tau, which harbors four MTBD repeats [120].”
A Novel Tau Antibody Detecting the First Amino-Terminal Insert Reveals Conformational Differences Among Tau Isoforms
Verelst, J., Geukens, N., Eddarkaoui, S., Vliegen, D., Smidt, E. D., Rosseels, J., Franssens, V., Molenberghs, S., François, C., Stoops, E., et al. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00048 · Cited by 11
“The largest Tau2N4R isoform was not detected, probably because its expression in normal or diseased adult brain is known to be very low (Goedert and Jakes, 1990; Buee et al., 2000).”
Background
Pathogenic MAPT mutations Q336H and Q336R have isoform‐dependent differences in aggregation propensity and microtubule dysfunction
Xia, Y., Nasif, L. H., & Giasson, B. I. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15358 · Cited by 9
“…total, the human brains express six major isoforms of tau: 0N3R, 1N3R, 2N3R, 0N4R, 1N4R, and 2N4R; with the 3R and 4R isoforms expressed at about equal ratio, while the 2N isoforms being less abundant (Boutajangout et al., 2004; Goedert & Jakes, 1990; Goedert et al., 1989; Wesseling et al., 2020).”
Background
iPS Cell-Based Model for MAPT Haplotype as a Risk Factor for Human Tauopathies Identifies No Major Differences in TAU Expression
Strauß, T., Marvian, A. T., Sadikoglou, E., Dhingra, A., Wegner, F., Trümbach, D., Wurst, W., Heutink, P., Schwarz, S. C., & Höglinger, G. U. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.726866 · Cited by 13
Genotype-Specific Differences between Mouse CNS Stem Cell Lines Expressing Frontotemporal Dementia Mutant or Wild Type Human Tau
Orr, M. E., Pitstick, R., Canine, B., Ashe, K. H., & Carlson, G. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039328 · Cited by 9
“Only a single tau band migrating at ,52kDa, the known molecular weight of recombinant human tau 4R0N [35], remained after phosphatase treatment in both mutant and wild type samples (Figure 4B).”
Background
Tau and saitohin gene expression pattern in progressive supranuclear palsy
Ezquerra, M., Gaig, C., Ascaso, C., Muñoz, E., & TOLOSA, E. S. (2007) · Brain Research · doi:10.1016/j.brainres.2007.01.098 · Cited by 9
Developmental regulation and PKC dependence of Alzheimer's-type tau phosphorylations in cultured fetal rat hippocampal neurons
Combs, C. K., Coleman, P. D., & O’Banion, M. K. (1998) · Developmental Brain Research · doi:10.1016/s0165-3806(98)00019-4 · Cited by 9
Protein kinases involved in the phosphorylation of human tau protein in transfected COS-1 cells
Medina, M., Garcı́a-Rocha, M., Padilla, R., Pérez, M., de Garcini, E. M., & Ávila, J. (1996) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/0925-4439(96)00018-x · Cited by 9
Chemically synthesized 182–235 segment of tau protein and analogue peptides are efficient in vitro microtubule assembly inducers of low apparent sequence specificity
Novella, I. S., Andreu, J. M., & Andreu, D. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81110-8 · Cited by 9
Heterogeneity of tau protein and mRNA expression during the development of cerebellar granule cell neurons in vitro
Przyborski, S. A., & Cambray-Deakin, M. A. (1995) · Developmental Brain Research · doi:10.1016/0165-3806(95)00050-n · Cited by 9
Human Tau Transgenic Mice
Götz, J., Tolnay, M., Barmettler, R., Ferrari, A., Bürki, K., Goedert, M., Probst, A., & Nitsch, R. M. (2001) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1249-3_6 · Cited by 9
Self-citation
Increase in wasteosomes (corpora amylacea) in frontotemporal lobar degeneration with specific detection of tau, TDP-43 and FUS pathology
Alsina, R., Riba, M., Pérez‐Millan, A., Borrego‐Écija, S., Aldecoa, I., Romera, C., Balasa, M., Antonell, A., Lladó, A., Compta, Y., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01812-0 · Cited by 10
“Notably, 4R tau assemble more rapidly than 3R tau and are also preferentially engulfed by astrocytes [15, 18].”
Background
Guidelines for the use and interpretation of Alzheimer’s disease biomarkers in clinical practice in Brazil: recommendations from the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology
Studart‐Neto, A., Barbosa, B. J. A. P., Coutinho, A. M., de Souza, L. C., Schilling, L. P., da Silva, M. N. M., Castilhos, R. M., Bertolucci, P. H. F., Borelli, W. V., Gomes, H. R., et al. (2024) · Dementia & Neuropsychologia · doi:10.1590/1980-5764-dn-2024-c001 · Cited by 11
Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research
Szegvari, E., Holec, S. A. M., & Woerman, A. L. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70021 · Cited by 8
“Expression of these 6 isoforms varies by age and brain region, with a notable shift from 0N3R expression during infancy to a more balanced 3R:4R expression in adulthood (Goedert and Jakes 1990; Hefti et al. 2018; Majounie et al. 2013; Trabzuni et al. 2012).”
Decoding tau acetylation in Alzheimer’s disease and tauopathies: from site-specific mechanisms to therapeutic horizons
Oh, Y. R., & Shin, M. (2025) · BMB Reports · doi:10.5483/bmbrep.2025-0077 · Cited by 9
Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation
Xia, Y., Bell, B. M., Kim, J. D., & Giasson, B. I. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1181804 · Cited by 8
“In terms of MT binding and regulation, both 3R and 4R tau isoforms have distinctively different physiologic roles (Goedert and Jakes, 1990; Goode et al., 2000; Panda et al., 2003).”
Background
The Role of Aβ and Tau Oligomers in the Pathogenesis of Alzheimer’s Disease
Bhaskar, K., & Lamb, B. T. (2011) · Springer eBooks · doi:10.1007/978-94-007-2774-8_5 · Cited by 8
Genetic and Molecular Aspects of Frontotemporal Lobar Degeneration
Haapasalo, A., & Remes, A. M. (2014) · Current Genetic Medicine Reports · doi:10.1007/s40142-014-0063-5 · Cited by 9
“Normally, 3R-tau and 4R-tau isoforms are expressed at 1:1 ratio in the adult human brain [10–12].”
Background
Tau Isoforms Expression in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis
Usarek, E., Kuźma‐Kozakiewicz, M., Schwalenstöcker, B., Kaźmierczak, B., Münch, C., Ludolph, A. C., & Barańczyk‐Kuźma, A. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9057-3 · Cited by 8
“In agreement with other authors [14, 28], we found that the C-terminal insert encoded by exon 10 was present in wild type adult mice (64- and 120-day-old).”
Result
Microtubule-associated protein tau in bovine retinal photoreceptor rod outer segments: Comparison with brain tau
Yamazaki, A., Nishizawa, Y., Matsuura, I., Hayashi, F., Usukura, J., & Bondarenko, V. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.021 · Cited by 8
“This inconsistency is also observed in human brain tau isoforms [8,51].”
Background
Tau isoform expression in frontotemporal dementia without tau deposition
Sutherland, G. T., Nowak, G., Halliday, G. M., & Kril, J. J. (2007) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2006.10.009 · Cited by 8
Secondary structures transition of tau protein with intrinsically disordered proteins specific force field
Dan, A., & Chen, H. (2018) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13407 · Cited by 8
The Levels of Tau Isoforms Containing Exon-2 and Exon-10 Segments Increased in the Cerebrospinal Fluids of the Patients with Sporadic Creutzfeldt-Jakob Disease
Chen, C., Zhou, W., Lv, Y., Shi, Q., Wang, J., Xiao, K., Chen, L., Zhang, B., & Dong, X. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9348-2 · Cited by 8
Expression of Concern: Transient expression of fluorescent tau proteins promotes process formation in PC12 cells: Contributions of the tau C‐terminus to this process
Yu, J.-Z., Kuret, J., & Rasenick, M. M. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10152 · Cited by 8
“Previous studies have shown that the inclusion of the fourth repeat increased the ability of tau to promote in vitro MT assembly and to stabilize MTs in cells (Goedert and Jakes, 1990; Lee and Rook, 1992).”
Background
Tau post-translational modifications in Alzheimer's disease: Insights into pathogenesis, therapeutic strategies, and diagnostic advances
Lei, H., Chen, X., Ruan, L., Liu, X., Ye, F., Li, K., Cheng, W., Yu, B., Di, C., & Di, C. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102927 · Cited by 7
Proximity Labeling of the Tau Repeat Domain Enriches RNA-Binding Proteins That Are Altered in Alzheimer's Disease and Related Tauopathies
Shapley, S. M., Shantaraman, A., Gadhavi, J. D., Kearney, M. A., Dammer, E. B., Duong, D. M., Bowen, C. A., Watson, C. M., Bagchi, P., Guo, Q., et al. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101458 · Cited by 9
Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders
Tang, F., Wei, J., Wong, M.-L., & Lei, P. (2025) · Genomic psychiatry : · doi:10.61373/gp025i.0122 · Cited by 7
The splice of life: how alternative splicing shapes regulatory and phenotypic evolution
Hunter, C. E., & Xing, Y. (2026) · The EMBO Journal · doi:10.1038/s44318-025-00666-z · Cited by 9
“…exons 2, 3, and 10: the inclusion of exon 2 together with the inclusion or skipping of exon 3 creates tau isoforms with 2N or 1N N-terminal inserts, and the inclusion or skipping of exon 10 creates tau isoforms with 4R or 3R microtubule-binding repeats (Andrea-dis, 2005; Goedert and Jakes, 1990).”
Dopamine-Induced Tau Modification Prevents Pathological Phosphorylation and Generates a Distinct Fibril Polymorph
Liu, Z., Li, X., Wang, Q., Liu, K., Zeng, W., Li, D., Zhao, K., Ma, Y., Long, H., Zhang, S., et al. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c22156 · Cited by 7
Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer’s disease
Lu, S., Qiu, S., Yu, G., Zhang, A., & Zhao, Q. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103097 · Cited by 8
Advances in the drug treatment of Alzheimer’s disease: pathophysiology and mechanisms of action
Nowell, J., Crook, H., de Leon, M. J., & Edison, P. (2026) · BMJ · doi:10.1136/bmj-2023-078881 · Cited by 7
Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System
Koppisetti, R. K., Barthélemy, N. R., Horie, K., Ly, C. V., Roberts, K. F., Koutarapu, S., Perrin, R. J., Franklin, E. E., Pedicone, C., Orrick, J., et al. (2026) · Annals of Neurology · doi:10.1002/ana.78300 · Cited by 7
“27,66 We observed a signi ﬁ cant decrease in the 4R isoform (residue 720 – 738) levels in the spinal cord (0.49 (cid:4) 0.09 normalized to total-tau, p < 0.0001) and SN lysates (0.38 (cid:4) 0.20, p < 0.0001) compared to the brain (0.66 (cid:4) 0.23; see Fig 3B).”
Influential
Developmental regulation of cardiac MAP4 protein expression
Webster, D. R., & Bratcher, J. M. (2006) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20140 · Cited by 7

Authors: Goedert, M., & Jakes, R.
Affiliations: MRC Laboratory of Molecular Biology (GB)
ORCID: Goedert, M.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 1990-12-01
Volume: 9
Issue: 13
Pages: 4225-4230
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1002/j.1460-2075.1990.tb07870.x
PMC: PMC552204
OpenAlex: W1509571186
Cited by: 929
References: 46
Citations by year: 2026: 23 · 2025: 29 · 2024: 50 · 2023: 39 · 2022: 40 · 2021: 53 · 2020: 34 · 2019: 39 · 2018: 42 · 2017: 41 · 2016: 27 · 2015: 37 · 2014: 18 · 2013: 21 · 2012: 25
FWCI: 15.03
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: tau protein, tau isoforms, microtubule-associated proteins, microtubule assembly, tandem repeats, recombinant protein expression, cerebral cortex, fetal brain
MeSH terms: Aged, Alkaline Phosphatase, Alzheimer Disease, Amino Acid Sequence, Brain, Escherichia coli, Humans, Isomerism, Microtubule-Associated Proteins, Middle Aged, Molecular Sequence Data, Recombinant Proteins, Repetitive Sequences, Nucleic Acid, RNA Splicing, RNA, Messenger, Tubulin, Mutagenesis, Site-Directed, tau Proteins

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Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.

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