Imatinib methanesulfonate reduces hyperphosphorylation of tau following repeated peripheral exposure to lipopolysaccharide
Abstract
For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aβ) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aβ in response to LPS, thereby preventing the buildup of Aβ in the hippocampus, and rescuing the cognitive dysfunction that normally follows. The present study aimed to examine the link between Aβ and tau following inflammation, and to expand our understanding of how IM affects AD pathology. Specifically, we hypothesized that the IM-mediated inhibition of Aβ production following inflammation would successfully protect against the hyperphosphorylation of tau (ptau). Here we show that 7days of LPS treatment in male C57BL/6J mice, which normally produces elevations in peripheral and central Aβ, also produces hyperphosphorylation of tau. However, just as pre-treatment and concurrent treatment with IM blocks Aβ production, it also blocks the phosphorylation of tau. In addition, 7days of LPS-induced inflammation and Aβ production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aβ that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aβ initiates tau phosphorylation.
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Microglial activation can induce tau accumulation in wild-type mice with no induced tauopathy.
“microglial activation can even induce tau accumulation in wild-type mice with no induced tauopathy [112]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [112]
Microglia-mediated inflammation is important in initiating tau pathology.
“strongly supporting the importance of microglia-mediated inflammation in initiating tau pathology”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [112]
Endotoxin promotes amyloid β and tau aggregation and neuropathology.
“Endotoxin promotes amyloid β and tau aggregation and neuropathology”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [68]
Endotoxin may promote the production or aggregation of amyloid β, tau and α-synuclein.
“Endotoxin may also promote the production or aggregation of amyloid β [66–68], tau [68, 69] and α-synuclein [70, 71].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [68]
Cites
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069 · see citing works
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · see citing works
2013 Alzheimer's disease facts and figures
Thies, W. H., & Bleiler, L. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.02.003 · Cited by 3,331 · see citing works
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052 · see citing works
Lee, V. M.-Y., Goedert, M., & Trojanowski, J. Q. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.1121 · Cited by 2,480 · see citing works
Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208 · see citing works
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188 · see citing works
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1503 · Cited by 1,561 · see citing works
Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils
Götz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001) · Science · doi:10.1126/science.1062097 · Cited by 1,526 · see citing works
Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease
Ittner, L. M., & Götz, J. (2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2967 · Cited by 1,357 · see citing works
Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?
Klein, W. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01749-5 · Cited by 989 · see citing works
De Felice, F. G., Velasco, P. T., Lambert, M. P., Viola, K., Fernandez, S. J., Ferreira, S. T., & Klein, W. L. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607483200 · Cited by 882 · see citing works
Lee, J. W., Lee, Y. K., Yuk, D. Y., Choi, D. Y., Ban, S. B., Oh, K. W., & Hong, J. T. (2008) · Journal of Neuroinflammation · doi:10.1186/1742-2094-5-37 · Cited by 772 · see citing works
Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease.
Alonso, A. C., Zaidi, T., Grundke-Iqbal, I., & Iqbal, K. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.12.5562 · Cited by 738 · see citing works
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2868-05.2005 · Cited by 697 · see citing works
β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding
Busciglio, J., Lorenzo, A., Yeh, J., & Yankner, B. A. (1995) · Neuron · doi:10.1016/0896-6273(95)90232-5 · Cited by 595 · see citing works
Hutchinson, E. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn2985 · Cited by 534 · 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
Holcomb, L. A., Gordon, M. N., Jantzen, P., Hsiao, K., Duff, K., & Morgan, D. (1999) · Behavior Genetics · doi:10.1023/a:1021691918517 · Cited by 353 · see citing works
Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease
He, G., Luo, W., Li, P., Remmers, C. L., Netzer, W. J., Hendrick, J. P., Bettayeb, K., Flajolet, M., Gorelick, F. S., Wennogle, L. P., et al. (2010) · Nature · doi:10.1038/nature09325 · Cited by 326 · see citing works
Wischik, C. M., Staff, R. T., Wischik, D. J., Bentham, P., Murray, A. D., Storey, J. M. D., Kook, K. A., & Harrington, C. R. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142874 · Cited by 269 · see citing works
Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism
Stancu, I.-C., Vasconcelos, B., Terwel, D., & Dewachter, I. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-51 · Cited by 256 · see citing works
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
Effect of LPS on the permeability of the blood–brain barrier to insulin
Xaio, H., Banks, W. A., Niehoff, M. L., & Morley, J. E. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03247-9 · Cited by 231 · see citing works
Adult-derived neural precursors transplanted into multiple regions in the adult brain
Herrera, D. G., García‐Verdugo, J. M., & Álvarez-Buylla, A. (1999) · Annals of Neurology · doi:10.1002/1531-8249(199912)46:6 · Cited by 204 · see citing works
Kahn, M. S., Kranjac, D., Alonzo, C. A., Haase, J. H., Cedillos, R. O., McLinden, K. A., Boehm, G. W., & Chumley, M. J. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.01.010 · Cited by 177 · see citing works
Self-citationSutcliffe, J. G., Hedlund, P. B., Thomas, E. A., Bloom, F. E., & Hilbush, B. S. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22603 · Cited by 115 · see citing works
c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice
Cancino, G. I., Perez de Arce, K., Castro, P. U., Toledo, E. M., von Bernhardi, R., & Alvarez, A. R. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.07.007 · Cited by 110 · see citing works
Are Tangles as Toxic as They Look?
Spires‐Jones, T. L., Kopeikina, K. J., Koffie, R. M., de Calignon, A., & Hyman, B. T. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9566-7 · Cited by 110 · see citing works
Dunning, C. J. R., McGauran, G., Willén, K. I., Gouras, G. K., O’Connell, D. J., & Linse, S. S. (2015) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5b00262 · Cited by 59 · see citing works
Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid β-peptide
Yan, S. D., Roher, A. E., Chaney, M., Zloković, B. V., Schmidt, A. M., & Stern, D. M. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00041-7 · Cited by 58 · see citing works
Weintraub, M. K., Bisson, C. M., Nouri, J. N., Vinson, B. T., Eimerbrink, M. J., Kranjac, D., Boehm, G. W., & Chumley, M. J. (2013) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2013.05.002 · Cited by 54 · see citing works
Self-citationWeintraub, M. K., Kranjac, D., Eimerbrink, M. J., Pearson, S. J., Vinson, B. T., Patel, J., Summers, W. M., Parnell, T. B., Boehm, G. W., & Chumley, M. J. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.03.009 · Cited by 35 · see citing works
Self-citationOvercoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn
Wang, H., Ren, C. H., Gunawardana, C. G., & Schmitt‐Ulms, G. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-24 · Cited by 18 · see citing works
Kaucsár, T., Bödör, C., Godó, M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092004 · Cited by 13 · see citing works
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“Fascinatingly, microglial activation can even induce tau accumulation in wild-type mice with no induced tauopathy [112], strongly supporting the importance of microglia-mediated inflammation in initiating tau pathology.”
BackgroundIntersection of pathological tau and microglia at the synapse
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- Authors
- Gardner, L. E., White, J. D., Eimerbrink, M. J., Boehm, G. W., & Chumley, M. J.
- Affiliations
- Texas Christian University (US)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 331
- Pages
- 72-77
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2438137602
- Cited by
- 29
- References
- 37
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 1 · 2016: 2
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Texas Christian University Science and Engineering Research Committee
- TCU Research and Creative Activity
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau hyperphosphorylation, lipopolysaccharide, Alzheimer's disease, amyloid-beta, neuroinflammation, hippocampus, tau pathology, cognitive impairment
- MeSH terms
- Imatinib Mesylate, Animals, Body Weight, Disease Models, Animal, Hippocampus, Lipopolysaccharides, Male, Mice, Inbred C57BL, Phosphorylation, Blotting, Western, Amyloid beta-Peptides, tau Proteins, Protein Kinase Inhibitors
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