Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability
Abstract
Tau inclusions play a key role in the pathogenesis of tauopathies. Altered tau levels have been detected in retina and optic nerve of patients with glaucoma, suggesting the possibility of shared pathogenic mechanisms with tauopathies. Here we report that hyperphosphorylated transgenic tau accumulates in the nerve fibre layer and, from 2 months of age, aggregates into filamentous inclusions in retinal ganglion cells of human P301S tau transgenic mice. Axonopathy and accumulation of hyperphosphorylated tau in the nerve fibre layer preceded inclusion formation. Hyperphosphorylated tau and tau inclusions were also detected in cultured retinal explants from 5-month-old transgenic mice. Axonal outgrowth was similar in transgenic and wild-type retinal explants under basal conditions. However, when exposed to growth-promoting stimuli, axon elongation was enhanced in explants from wild-type but not transgenic mice, indicating that the presence of abnormal tau can impair stimulated axonal outgrowth. These findings suggest that the retina is a good model system for investigating tau-driven neurodegeneration and for assessing potential pharmacological modifiers for tauopathies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 may alter axonal transport.
“These observations suggest that tau may alter axonal transport.”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Gasparini et al., 2011
Cites
CellProfiler: image analysis software for identifying and quantifying cell phenotypes
Carpenter, A. E., Jones, T. R., Lamprecht, M. R., Clarke, C., Kang, I. H., Friman, O., Guertin, D. A., Chang, J. H., Lindquist, R. A., Moffat, J., et al. (2006) · Genome biology · doi:10.1186/gb-2006-7-10-r100 · Cited by 5,077 · see citing works
Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP
Feng, G., Mellor, R. H., Bernstein, M., Keller-Peck, C., Nguyen, Q. T., Wallace, M., Nerbonne, J. M., Lichtman, J. W., & Sanes, J. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)00084-2 · Cited by 3,042 · see citing works
Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D., & Crowther, R. A. (1989) · Neuron · doi:10.1016/0896-6273(89)90210-9 · Cited by 2,492 · see citing works
Self-citationNeuN, a neuronal specific nuclear protein in vertebratesxs
Mullen, R. J., Buck, C. R., & Smith, A. M. (1992) · Development · doi:10.1242/dev.116.1.201 · Cited by 2,351 · see citing works
A Century of Alzheimer's Disease
Goedert, M., & Spillantini, M. G. (2006) · Science · doi:10.1126/science.1132814 · Cited by 2,106 · see citing works
Self-citationDesign and validation of a tool for neurite tracing and analysis in fluorescence microscopy images
Meijering, E. H. W., Jacob, M., Sarria, J. ‐. F., Steiner, P., Hirling, H., & Unser, M. A. (2004) · Cytometry Part A · doi:10.1002/cyto.a.20022 · Cited by 1,611 · see citing works
Lewis, J., McGowan, E., Rockwood, J., Melrose, H., Nacharaju, P., Van Slegtenhorst, M., Gwinn-Hardy, K., Murphy, M. P., Baker, M., Yu, X., et al. (2000) · Nature Genetics · doi:10.1038/78078 · Cited by 1,371 · see citing works
Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer’s Disease
Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., Raman, R., Davies, P., Masliah, E., Williams, D. S., et al. (2005) · Science · doi:10.1126/science.1105681 · Cited by 1,214 · see citing works
Differential Regulation of Dynein and Kinesin Motor Proteins by Tau
Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. F. (2008) · Science · doi:10.1126/science.1152993 · Cited by 1,012 · see citing works
Mandelkow, E., & Mandelkow, E. (1998) · Trends in Cell Biology · doi:10.1016/s0962-8924(98)01368-3 · Cited by 951 · see citing works
Meyer‐Franke, A., Kaplan, M. R., Pfrieger, F. W., & Barres, B. A. (1995) · Neuron · doi:10.1016/0896-6273(95)90172-8 · Cited by 852 · see citing works
Bancher, C., Brunner, C., Lassmann, H., Budka, H., Jellinger, K., Wiche, G., Seitelberger, F., Grundke-Iqbal, I., Iqbal, K., & Wisniewski, H. M. (1989) · Brain Research · doi:10.1016/0006-8993(89)91396-6 · Cited by 818 · see citing works
Braak, F., Braak, H., & Mandelkow, E. (1994) · Acta Neuropathologica · doi:10.1007/bf00293315 · Cited by 769 · see citing works
Allen, B., Ingram, E., Takao, M., Smith, M. J., Jakes, R., Virdee, K., Yoshida, H., Holzer, M., Craxton, M., Emson, P. C., et al. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09340.2002 · Cited by 746 · see citing works
Self-citationGasparini, L., Gouras, G. K., Wang, R., Gross, R. S., Beal, M. F., Greengard, P., & Xu, H. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-08-02561.2001 · Cited by 493 · see citing works
Self-citationMonoclonal 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 · see citing works
Self-citationJackson, G. R., Wiedau-Pazos, M., Sang, T.-K., Wagle, N., Brown, C. A., Massachi, S., & Geschwind, D. H. (2002) · Neuron · doi:10.1016/s0896-6273(02)00706-7 · Cited by 488 · see citing works
Retinal Ganglion Cells Do Not Extend Axons by Default
Goldberg, J. L., Espinosa, J. S., Xu, Y., Davidson, N., Kovacs, G. T. A., & Barres, B. A. (2002) · Neuron · doi:10.1016/s0896-6273(02)00602-5 · Cited by 452 · see citing works
Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma
Buckingham, B. P., Inman, D. M., Lambert, W. S., Oglesby, E., Calkins, D. J., Steele, M. R., Vetter, M. L., Marsh‐Armstrong, N., & Horner, P. J. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4443-07.2008 · Cited by 415 · see citing works
Spittaels, K., den Haute, C. V., Dorpe, J. V., Bruynseels, K., Vandezande, K., Laenen, I., Geerts, H., Mercken, M., Sciot, R., Lommel, A. V. V., et al. (1999) · American Journal of Pathology · doi:10.1016/s0002-9440(10)65533-2 · Cited by 405 · see citing works
İşeri, P., Altıntaş, Ö., Tokay, T., & Yüksel, N. (2006) · Journal of Neuro-Ophthalmology · doi:10.1097/01.wno.0000204645.56873.26 · Cited by 400 · see citing works
Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein
Probst, A., Götz, J., Wiederhold, K., Tolnay, M., Mistl, C., Jaton, A., Hong, M., Ishihara, T., Lee, V., Trojanowski, J., et al. (2000) · Acta Neuropathologica · doi:10.1007/s004010051148 · Cited by 362 · see citing works
Self-citationStraight and paired helical filaments in Alzheimer disease have a common structural unit.
Crowther, R. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.6.2288 · Cited by 354 · see citing works
Optic Nerve Damage in Alzheimer's Disease
Sadun, A. A., & Bassi, C. J. (1990) · Ophthalmology · doi:10.1016/s0161-6420(90)32621-0 · Cited by 351 · see citing works
Inducible Expression of Tau Repeat Domain in Cell Models of Tauopathy
Khlistunova, I., Biernat, J., Wang, Y., Pickhardt, M., von Bergen�, M., Gažová, Z., Mandelkow�, E., & Mandelkow, E. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507753200 · Cited by 350 · see citing works
Targeting amyloid-β in glaucoma treatment
Guo, L., Salt, T. E., Luong, V., Wood, N. W., Cheung, W., Maaß, A., Ferrari, G., Russo‐Marie, F., Sillito, A. M., Cheetham, M. E., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703707104 · Cited by 342 · see citing works
Nishimura, I., Yang, Y., & Lu, B. (2004) · Cell · doi:10.1016/s0092-8674(04)00170-9 · Cited by 324 · see citing works
Schlamp, C. L., Li, Y., Dietz, J. A., Janssen, K. T., & Nickells, R. W. (2006) · BMC Neuroscience · doi:10.1186/1471-2202-7-66 · Cited by 303 · see citing works
Amyloid-β Deposits Lead to Retinal Degeneration in a Mouse Model of Alzheimer Disease
Ning, A., Cui, J., To, E., Ashe, K. H., & Matsubara, J. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-1849 · Cited by 303 · see citing works
Retinal ganglion cell degeneration in Alzheimer's disease
Blanks, J. C., Hinton, D. R., Sadun, A. A., & Miller, C. A. (1989) · Brain Research · doi:10.1016/0006-8993(89)90653-7 · Cited by 297 · see citing works
Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension.
McKinnon, S. J., Lehman, D. M., Kerrigan, L. A., Merges, C. A., Pease, M. E., Kerrigan, D., Ransom, N. L., Tahzib, N. G., Reitsamer, H. A., Levkovitch-Verbin, H., et al. (2002) · PubMed · Cited by 296 · see citing works
Age-Dependent Neurodegeneration and Alzheimer-Amyloid Plaque Formation in Transgenic Drosophila
Greeve, I., Kretzschmar, D., Tschäpe, J., Beyn, A., Brellinger, C., Schweizer, M., Nitsch, R. M., & Reifegerste, R. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0283-04.2004 · Cited by 284 · see citing works
Tau phosphorylation and aggregation in Alzheimer's disease pathology
Ávila, J. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.02.067 · Cited by 283 · see citing works
Perez, S. E., Lumayag, S., Kovacs, B., Mufson, E. J., & Xu, S. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-2384 · Cited by 231 · see citing works
Visual dysfunction, neurodegenerative diseases, and aging
Jackson, G. R., & Owsley, C. (2003) · Neurologic Clinics · doi:10.1016/s0733-8619(02)00107-x · Cited by 226 · see citing works
Bellucci, A., Westwood, A. J., Ingram, E., Casamenti, F., Goedert, M., & Spillantini, M. G. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63421-9 · Cited by 215 · see citing works
Self-citationRetinal Ganglion Cells Lose Trophic Responsiveness after Axotomy
Shen, S., Wiemelt, A. P., McMorris, F. A., & Barres, B. A. (1999) · Neuron · doi:10.1016/s0896-6273(00)80780-1 · Cited by 207 · see citing works
Wang, Y. P., Biernat, J., Pickhardt, M., Mandelkow�, E., & Mandelkow�, E. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703676104 · Cited by 205 · see citing works
Tau protein, the paired helical filament and Alzheimer's disease
Goedert, M., Klug, A., & Crowther, R. A. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s323 · Cited by 195 · see citing works
Self-citationAxonal Transport RatesIn VivoAre Unaffected by Tau Deletion or Overexpression in Mice
Yuan, A., Kumar, A. R., Peterhoff, C. M., Duff, K., & Nixon, R. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5242-07.2008 · Cited by 187 · see citing works
Interaction of tau protein with the dynactin complex
Magnani, E., Fan, J., Gasparini, L., Golding, M., Williams, M., Schiavo, G., Goedert, M., Amos, L., & Spillantini, M. G. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601878 · Cited by 186 · see citing works
Self-citationβ-Amyloid Induces Paired Helical Filament-like Tau Filaments in Tissue Culture
Ferrari, A., Hoerndli, F. J., Baechi, T., Nitsch, R. M., & Götz, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308243200 · Cited by 182 · see citing works
Periaqueductal gray matter projections to midline and intralaminar thalamic nuclei of the rat
Krout, K. E., & Loewy, A. D. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20000814)424:1 · Cited by 180 · see citing works
Vitreous fluid levels of β-amyloid(1–42) and tau in patients with retinal diseases
Yoneda, S., Hara, H., Hirata, A., Fukushima, M., Inomata, Y., & Tanihara, H. (2005) · Japanese Journal of Ophthalmology · doi:10.1007/s10384-004-0156-x · Cited by 168 · 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
Sun, A.-Y., Nguyen, X. V., & Bing, G. (2002) · Journal of Histochemistry and Cytochemistry · doi:10.1177/002215540205000403 · Cited by 146 · 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
Retinal tau pathology in human glaucomas
Gupta, N., Fong, J., Ang, L. C., & Yücel, Y. H. (2008) · Canadian Journal of Ophthalmology · doi:10.3129/i07-185 · Cited by 134 · see citing works
Vogelsberg-Ragaglia, V., BRUCE, J. S., Richter‐Landsberg, C., Zhang, B., Hong, M., Trojanowski, J. Q., & Lee, V. M. ‐. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.12.4093 · Cited by 129 · see citing works
Parisi, V. (2003) · Seminars in Ophthalmology · doi:10.1076/soph.18.2.50.15855 · Cited by 126 · see citing works
Beirowski, B., Berek, L., Adalbert, R., Wagner, D. A., Grumme, D., Addicks, K., Ribchester, R. R., & Coleman, M. P. (2003) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2003.10.016 · Cited by 122 · see citing works
Self-citationIqbal, K., & Grundke, I. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s325 · Cited by 110 · see citing works
Formation of aberrant phosphotau fibrillar polymers in neural cultured cells
Pérez, M., Hernández, F., Gómez‐Ramos, A., Smith, M. A., Perry, G. L., & Ávila, J. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.02794.x · Cited by 103 · see citing works
Dubey, M., Chaudhury, P., Kabiru, H., & Shea, T. B. (2007) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20243 · Cited by 91 · see citing works
Yoshida, H., & Goedert, M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04052.x · Cited by 83 · see citing works
Self-citationFluoro-substituted and 13C-labeled styrylbenzene derivatives for detecting brain amyloid plaques
Sato, K., Higuchi, M., Iwata, N., Saido, T. C., & Sasamoto, K. (2004) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2004.02.013 · Cited by 82 · see citing works
Tau binding to microtubules does not directly affect microtubule‐based vesicle motility
Morfini, G. A., Pigino, G. F., Mizuno, N., Kikkawa, M., & Brady, S. T. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21154 · Cited by 81 · see citing works
Frontotemporal Dementia with Tau Pathology
Gasparini, L., Terni, B., & Spillantini, M. G. (2007) · Neurodegenerative Diseases · doi:10.1159/000101848 · Cited by 74 · see citing works
Self-citationVelasco, A. L., Fraser, G. M., Delobel, P., Ghetti, B. F., Lavenir, I., & Goedert, M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.02.025 · Cited by 40 · see citing works
Self-citationAssembly of filamentous tau aggregates in human neuronal cells
Ko, L., Rush, T., Sahara, N., Kersh, J. S., Easson, C., Deture, M. A., Lin, W.-L., Connor, Y., & Yen, S.-H. C. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2004-6605 · Cited by 33 · see citing works
Bates, C. A., & Meyer, R. (1993) · Experimental Neurology · doi:10.1006/exnr.1993.1027 · Cited by 27 · see citing works
Changes in Thy-1 antigen immunoreactivity in the rat retina during pre- and postnatal development
Schmid, S., Guenther, E., & Köhler, K. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)12020-5 · Cited by 21 · see citing works
Expression of Protein Markers of Alzheimer's Disease in Human Glaucoma Eyes
Tseng, H. C., Kasmala, L. T., Proia, A. D., et al. (2007) · Investigative Ophthalmology & Visual Science · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma.
Ramirez, A. I., de Hoz, R., Salobrar-Garcia, E., Salazar, J. J., Rojas, B., Ajoy, D., López-Cuenca, I., Rojas, P., Triviño, A., & Ramírez, J. M. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00214 · Cited by 466 · see citing works
Rorabaugh, J. M., Chalermpalanupap, T., Botz-Zapp, C. A., Fu, V. M., Lembeck, N. A., Cohen, R. M., & Weinshenker, D. (2017) · Brain · doi:10.1093/brain/awx232 · Cited by 227 · see citing works
Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy
Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., Marotta, R., Xu, H., & Gasparini, L. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0082-7 · Cited by 126 · see citing works
Self-citationChang, L. Y. L., Lowe, J., Ardiles, A., Lim, J., Grey, A. C., Robertson, K., Danesh‐Meyer, H., Palacios, A. G., & Acosta, M. L. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.06.004 · Cited by 106 · see citing works
Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy
Dapper, J. D., Crish, S. D., Pang, I.-H., & Calkins, D. J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.001 · Cited by 76 · see citing works
Schlegel, K., Awwad, K., Heym, R. G., Holzinger, D., Doell, A., Barghorn, S., Jahn, T. R., Klein, C., Mordashova, Y., Schulz, M., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0831-2 · Cited by 30 · see citing works
Self-citation
- Authors
- Gasparini, L., Anthony Crowther, R., Martin, K. R., Berg, N., Coleman, M., Goedert, M., & Spillantini, M. G.
- Affiliations
- University of Cambridge (GB)
- Babraham Institute (GB)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Gasparini, Laura
- Spillantini, Maria Grazia
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 32
- Issue
- 3
- Pages
- 419-433
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2023985004
- Cited by
- 133
- References
- 63
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 13 · 2023: 9 · 2022: 10 · 2021: 21 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 8 · 2016: 15 · 2015: 4 · 2014: 8 · 2013: 7 · 2012: 6
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Alzheimer's Research Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Keywords
- tau inclusions, P301S tau, tauopathy, retinal ganglion cells, axonopathy, hyperphosphorylated tau, glaucoma, axon growth, tau transgenic mice, retinal explants, neurodegeneration
- MeSH terms
- Analysis of Variance, Animals, Axons, Bacterial Proteins, Inclusion Bodies, Disease Models, Animal, Humans, Luminescent Proteins, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Ophthalmoscopy, Organ Culture Techniques, Phosphorylation, Proline, Retinal Ganglion Cells, Serine, tau Proteins, Neurofilament Proteins, Tauopathies, Intercellular Signaling Peptides and Proteins, Microscopy, Electron, Transmission, Mice
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
