Rapid Tyrosine Phosphorylation of Neuronal Proteins Including Tau and Focal Adhesion Kinase in Response to Amyloid-β Peptide Exposure: Involvement of Src Family Protein Kinases
Open accessAbstract
The increased production of amyloid β-peptide (Aβ) in Alzheimer's disease is acknowledged to be a key pathogenic event. In this study, we examined the response of primary human and rat brain cortical cultures to Aβ administration and found a marked increase in the tyrosine phosphorylation content of numerous neuronal proteins, including tau and putative microtubule-associated protein 2c (MAP2c). We also found that paired helical filaments of aggregated and hyperphosphorylated tau are tyrosine phosphorylated, indicating that changes in the phosphotyrosine content of cytoplasmic proteins in response to Aβ are potentially an important process. Increased tyrosine phosphorylation of cytoskeletal and other neuronal proteins was specific to fibrillar Aβ 25–35 and Aβ 1–42. The tyrosine phosphorylation was blocked by addition of the Src family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-d)pyramide (PP2) and the phosphatidylinositol 3-kinase inhibitor LY 294002. Tyrosine phosphorylation of tau and MAP2c was concomitant with an increase in the tyrosine phosphorylation and subsequent putative activation of the non-receptor kinase, focal adhesion kinase (FAK). Immunoprecipitation of Fyn, a member of the Src family, from Aβ 25–35-treated neurons showed an increased association of Fyn with FAK. Aβ treatment of cells also stimulated the sustained activation of extracellular regulated kinase-2, which was blocked by addition of PP2 and LY 294002, suggesting that FAK/Fyn/PI3-kinase association is upstream of mitogen-activated protein (MAP) kinase signaling in Aβ-treated neurons. This cascade of signaling events contains the earliest biochemical changes in neurons to be described in response to Aβ exposure and may be critical for subsequent neurodegenerative changes.
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?
Rapid tyrosine phosphorylation of neuronal proteins including Tau and FAK can be observed in response to Aβ exposure involving Src family kinases.
“More specifically, rapid tyrosine phosphorylation of neuronal proteins including Tau and FAK can be observed in response to Aβ exposure involving Src family kinases [143].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [143]
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
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599 · see citing works
Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers
Schaeffer, H. J., & Weber, M. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.4.2435 · Cited by 1,600 · see citing works
Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404
Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., & Lee, V. M. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490390607 · Cited by 488 · cited 1× · see citing works
“The labeling by 4G10 was weaker than PHF-1, and it was found to be necessary to enrich for PHF-tau to observe clear labeling by 4G10, suggesting that the phosphotyrosine content is lower than the level of phosphorylation at the PHF-1 epitope (serines 396 and 404) (Otvos et al., 1994).”
Background
Flagged first, then by citations
Research works printed but not linked: 1
- MacManus A, Ramsden M, Murray M, Henderson Z, Pearson HA, Campbell VA (2000) Enhancement of (45) Ca (2ϩ) influx and voltage- dependent Ca(2ϩ) channel activity by beta-amyloid-(1-40) in rat cor- tical synaptosomes and cultured cortical neurons. Modulation by the proinflammatory cytokine interleukin-1beta. J Biol Chem 275:4713-4718.
Cited by
Sorted by citations
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Roberson, E. D., Halabisky, B., Yoo, J. W., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P., Devidze, N., Yu, G.-Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4152-10.2011 · Cited by 654 · see citing works
Tau protein kinases: Involvement in Alzheimer's disease
Martin, L., Latypova, X., Wilson, C. M., Magnaudeix, A., Perrin, M.-L., Yardin, C., & Terro, F. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.003 · Cited by 631 · see citing works
Cruz, J. C., Tseng, H.-C., Goldman, J. A., Shih, H., & Tsai, L.-H. (2003) · Neuron · doi:10.1016/s0896-6273(03)00627-5 · Cited by 609 · see citing works
The importance of tau phosphorylation for neurodegenerative diseases
Noble, W., Hanger, D. P., Miller, C. C. J., & Lovestone, S. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00083 · Cited by 475 · see citing works
Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers
De Felice, F. G., Wu, D., Lambert, M. P., Fernandez, S. J., Velasco, P. T., Lacor, P. N., Bigio, E. H., Jerecic, J., Acton, P. J., Shughrue, P. J., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.029 · Cited by 432 · see citing works
Chin, J., Palop, J. J., Puoliväli, J., Massaro, C., Bien-Ly, N., Gerstein, H., Scearce-Levie, K., Masliah, E., & Mucke, L. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2980-05.2005 · Cited by 312 · see citing works
Gupta, A., Bisht, B., & Dey, C. S. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.033 · Cited by 302 · see citing works
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · see citing works
Kontaxi, C., Piccardo, P., & Gill, A. C. (2017) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2017.00056 · Cited by 138 · see citing works
Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice
Leroy, K., Bretteville, A., Schindowski, K., Gilissen, E., Authelet, M., De Decker, R., Yilmaz, Z., Buée, L., & Brion, J.-P. (2007) · The American Journal of Pathology · doi:10.2353/ajpath.2007.070345 · Cited by 135 · see citing works
Dourlen, P., Fernandez-Gomez, F. J., Dupont, C., Grenier-Boley, B., Bellenguez, C., Obriot, H., Caillierez, R., Sottejeau, Y., Chapuis, J., Bretteville, A., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.59 · Cited by 118 · see citing works
Potential Contribution of Exosomes to the Prion-Like Propagation of Lesions in Alzheimer’s Disease
Vingtdeux, V., Sergeant, N., & Buée, L. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00229 · Cited by 116 · see citing works
Grace, E. A., & Busciglio, J. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00493.2003 · Cited by 113 · see citing works
Hernandez, P., Lee, G., Sjoberg, M., & Maccioni, R. B. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-0933 · Cited by 107 · see citing works
Hu, Z., Chen, P.-H., Li, W., Douglas, T., Hines, J., Liu, Y., & Crews, C. M. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c11706 · Cited by 98 · see citing works
Masitinib for the treatment of mild to moderate Alzheimer’s disease
Folch, J., Petrov, D., Ettcheto, M., Pedrós, I., Abad, S., Beas-Zarate, C., Lazarowski, A., Marin, M., Olloquequi, J., Auladell, C., et al. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.1045419 · Cited by 80 · see citing works
Pariante, C. M., Hye, A., Williamson, R., Makoff, A., Lovestone, S., & Kerwin, R. W. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300195 · Cited by 70 · see citing works
Self-citationPei, J.-J., Sjögren, M., & Winblad, B. (2008) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e328314b78b · Cited by 49 · see citing works
Retinoic acid isomers protect hippocampal neurons from amyloid-β induced neurodegeneration
Sahin, M., Karaüzüm, S. B., Perry, G., Smith, M. A., & Alicigüzel, Y. (2005) · Neurotoxicity Research · doi:10.1007/bf03036453 · Cited by 41 · see citing works
Masitinib for the Treatment of Alzheimer’s Disease
Ettcheto, M., Cano, A., Sanchez-López, E., Verdaguer, E., Folch, J., Auladell, C., & Camins, A. (2021) · Neurodegenerative Disease Management · doi:10.2217/nmt-2021-0019 · Cited by 28 · see citing works
Saleh, B., Srikanth, K. D., Sneh, T., Yue, L., Pelech, S., Elliott, E., & Gil-Henn, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169055 · Cited by 10 · see citing works
- Authors
- Williamson, R., Scales, T., Clark, B. R., Gibb, G., Reynolds, C. H., Kellie, S., Bird, I. N., Varndell, I. M., Sheppard, P. W., Everall, I., & Anderton, B. H.
- Affiliations
- King's College London (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-01-01
- Volume
- 22
- Issue
- 1
- Pages
- 10-20
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6757621
- OpenAlex
- W1841303832
- Cited by
- 227
- References
- 5
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 3 · 2012: 17
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Alzheimer's Society
- King's College London
- Medical Research Council
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, tyrosine phosphorylation, tau protein, focal adhesion kinase, Src family kinases, Fyn, MAP2c, paired helical filaments, phosphatidylinositol 3-kinase, ERK2, MAPK signaling, Alzheimer's disease, neuronal signaling, PP2, LY294002
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Cells, Cultured, Cytoskeletal Proteins, Enzyme Inhibitors, Humans, Microtubule-Associated Proteins, Neurons, Peptide Fragments, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Tyrosine, Signal Transduction, Amyloid beta-Peptides, tau Proteins, src-Family Kinases, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Caspases, Proto-Oncogene Proteins c-fyn, Rats, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1
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
