Spectroscopic Studies of GSK3β Phosphorylation of the Neuronal Tau Protein and Its Interaction with the N-Terminal Domain of Apolipoprotein E
Open accessAbstract
Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-β peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated Tau protein. Tau is mostly found in a hyperphosphorylated form in these tangles. Glycogen synthase kinase 3β (GSK3β) is a proline-directed kinase generally considered as one of the major players that (hyper)phosphorylates Tau. The kinase phosphorylates mainly (Ser/Thr)-Pro motifs and is believed to require a priming activity by another kinase. Here, we use an in vitro phosphorylation assay and NMR spectroscopy to characterize in a qualitative and quantitative manner the phosphorylation of Tau by GSK3β. We find that three residues can be phosphorylated (Ser-396, Ser-400, and Ser-404) by GSK3β alone, without priming. Ser-404 is essential in this process, as its mutation to Ala prevents all activity of GSK3β. However, priming enhances the catalytic efficacy of the kinase, as initial phosphorylation of Ser-214 by the cAMP-dependent protein kinase (PKA) leads to the rapid modification by GSK3β of four regularly spaced additional sites. Because the regular incorporation of negative charges by GSK3β leads to a potential parallel between phospho-Tau and heparin, we investigated its interaction with the heparin/low density lipoprotein receptor binding domain of human apolipoprotein E. We indeed observed an interaction between the GSK3β-promoted regular phospho-pattern on Tau and the apolipoprotein E fragment but none in the absence of phosphorylation or the presence of an irregular phosphorylation pattern by the prolonged activity of PKA. Apolipoprotein E is therefore able to discriminate and interact with specific phosphorylation patterns of Tau.
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?
ApoE4 activates LRP1 and subsequent intracellular signaling pathways, namely Wnt3/β-catenin/GSK3β pathway, that ultimately potentiates GSK3β-mediated tau hyperphosphorylation.
“ApoE4 activates LRP1 and subsequent intracellular signaling pathways, namely Wnt3/β-cathenin/GSK3β pathway, that ultimately potentiates GSK3β-mediated tau hyperphosphorylation [53,54]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [54]
In “GSK3β Phospho-Tau and Apolipoprotein E” (page unavailable), the paper reports that GSK3β phosphorylates Tau and that the resulting phosphorylation pattern permits interaction with an apoE3 fragment. It does not show that apoE4 activates LRP1 or Wnt3/β-catenin signaling, or that apoE4 potentiates Tau hyperphosphorylation; it says the mechanism linking apoE4 to disease remains controversial. (LLM, conf=0.84)
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
Braak, 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
Transmission and spreading of tauopathy in transgenic mouse brain
Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1901 · Cited by 1,803 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Frost, B., Jacks, R. L., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808759200 · Cited by 1,252 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Li, T., & Paudel, H. K. (2006) · Biochemistry · doi:10.1021/bi051634r · Cited by 140 · see citing works
Interaction of the N-Terminal Domain of Apolipoprotein E4 with Heparin
Dong, J., Peters-Libeu, C. A., Weisgraber, K. H., Segelke, B. W., Rupp, B., Capila, I., Hernáiz, M. J., LeBrun, L. A., & Linhardt, R. J. (2001) · Biochemistry · doi:10.1021/bi002417n · Cited by 99 · see citing works
Characterization of the Heparin Binding Sites in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Nguyen, D., Baldwin, F., Weisgraber, K. H., Wehrli, S., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213207200 · Cited by 90 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [28]28. Landrieu, I., Leroy, A., Smet-Nocca, C., Huvent, I., Amniai, L., Hamdane, M., Sibille, N., Bue ´e, L., Wieruszeski, J.-M., and Lippens, G. (2010) Biochem. Soc. Trans. 38, 1006-1011
- [31]31. Peterson, D. W., Ando, D. M., Taketa, D. A., Zhou, H., Dahlquist, F. W., and Lew, J. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 2884-2889 <!-- image --> ASBMB
Cited by
Sorted by citations
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157 · see citing works
Reddy, P. H. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.06.012 · Cited by 147 · see citing works
Dionísio, P. A., Amaral, J. D., Ribeiro, M. F., Lo, A. C., D'Hooge, R., & Rodrigues, C. M. P. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.034 · Cited by 127 · see citing works
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome
Tramutola, A., Lanzillotta, C., Di Domenico, F., Head, E., Butterfield, D. A., Perluigi, M., & Barone, E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104772 · Cited by 73 · see citing works
Structural Basis of Tau Interaction With BIN1 and Regulation by Tau Phosphorylation
Lasorsa, A., Malki, I., Cantrelle, F.-X., Merzougui, H., Boll, E., Lambert, J.-C., & Landrieu, I. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00421 · Cited by 58 · see citing works
Self-citation
- Authors
- Leroy, A., Landrieu, I., Huvent, I., Legrand, D., Codeville, B., Wieruszeski, J.-M., & Lippens, G.
- Affiliations
- Université Paris-Sud (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Leroy, Arnaud
- Lippens, Guy
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 285
- Issue
- 43
- Pages
- 33435-33444
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2963357
- OpenAlex
- W2094294016
- Cited by
- 86
- References
- 8
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 9 · 2013: 6 · 2012: 8
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- GSK3β, tau phosphorylation, tau hyperphosphorylation, apolipoprotein E, N-terminal domain, Alzheimer's disease, phosphorylated tau, heparin binding, protein-protein interaction
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Apolipoproteins E, Humans, Phosphorylation, tau Proteins, Protein Structure, Tertiary, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Substitution, Mutation, Missense, Glycogen Synthase Kinase 3
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
