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Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections
Open accessAbstract
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024-1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6-12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.
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“As mice have primarily monocular vision, with >95% of RGCs projecting into the contralateral side of the brain, the unaffected side of the visual system can serve as an internal control 26, 27”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [27]
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Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
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
Aston-Jones, G., & Cohen, J. D. (2005) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.28.061604.135709 · Cited by 4,472
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668
Berridge, C. W., & Waterhouse, B. D. (2003) · Brain Research Reviews · doi:10.1016/s0165-0173(03)00143-7 · Cited by 2,529
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
Self-citationSynapse 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
Self-citationStages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years
Braak, H., Thal, D. R., Ghebremedhin, E., & Del Tredici, K. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318232a379 · Cited by 2,194
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174
Self-citationTau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., et al. (2005) · Science · doi:10.1126/science.1113694 · Cited by 2,014
Nucleus locus ceruleus: new evidence of anatomical and physiological specificity
Foote, S. L., Bloom, F. E., & Aston-Jones, G. (1983) · Physiological Reviews · doi:10.1152/physrev.1983.63.3.844 · Cited by 1,901
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
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427
Moore, R. Y., & Bloom, F. E. (1979) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.02.030179.000553 · Cited by 1,378
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
Trans-Synaptic Spread of Tau Pathology In Vivo
Liu, L., Drouet, V., Wu, J., Witter, M. P., Small, S. A., Clelland, C. L. T., & Duff, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031302 · Cited by 994
Tuning arousal with optogenetic modulation of locus coeruleus neurons
Carter, M. E., Yizhar, O., Chikahisa, S., Nguyen, H., Adamantidis, A., Nishino, S., Deisseroth, K., & de Lecea, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2682 · Cited by 993
Tauopathy in Drosophila : Neurodegeneration Without Neurofibrillary Tangles
Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M., & Feany, M. B. (2001) · Science · doi:10.1126/science.1062382 · Cited by 939
The pathological process underlying Alzheimer’s disease in individuals under thirty
Braak, H., & Del Tredici, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-010-0789-4 · Cited by 812
Brain homogenates from human tauopathies induce tau inclusions in mouse brain
Clavaguera, F., Akatsu, H., Fraser, G. M., Crowther, R. A., Frank, S., Hench, J., Probst, A., Winkler, D. T., Reichwald, J., Staufenbiel, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301175110 · Cited by 792
Spreading of pathology in neurodegenerative diseases: a focus on human studies
Brettschneider, J., Tredici, K. D., Lee, V. M.-Y., & Trojanowski, J. Q. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3887 · Cited by 790
Self-citationThe Brain Nucleus Locus Coeruleus: Restricted Afferent Control of a Broad Efferent Network
Aston‐Jones, G., Ennis, M. J., Pieribone, V. A., Nickell, W. T., & Shipley, M. T. (1986) · Science · doi:10.1126/science.3775363 · Cited by 778
Iba, M., Guo, J. L., McBride, J. D., Zhang, B., Trojanowski, J. Q., & Lee, V. M.-Y. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2642-12.2013 · Cited by 664
Self-citationCell-to-cell transmission of pathogenic proteins in neurodegenerative diseases
Guo, J. L., & Lee, V. M. Y. (2014) · Nature Medicine · doi:10.1038/nm.3457 · Cited by 641
Self-citationSeeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles
Guo, J. L., & Lee, V. M.-Y. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209296 · Cited by 636
Self-citationWilcock, G. K., & Esiri, M. M. (1982) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(82)90155-1 · Cited by 608
Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique
Cedarbaum, J. M., & Aghajanian, G. K. (1978) · The Journal of Comparative Neurology · doi:10.1002/cne.901780102 · Cited by 553
Ahmed, Z., Cooper, J., Murray, T. K., Garn, K., McNaughton, E., Clarke, H., Parhizkar, S., Ward, M. A., Cavallini, A., Jackson, S., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1254-6 · Cited by 484
Ovbiagele, B. I., Kidwell, C. S., & Saver, J. L. (2005) · Cited by 454
Zhang, B., Carroll, J., Trojanowski, J. Q., Yao, Y., Iba, M., Potuzak, J. S., Hogan, A.-M. L., Xie, S. X., Ballatore, C., Smith, A. B., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.4922-11.2012 · Cited by 401
Self-citationNeurons May Live for Decades with Neurofibrillary Tangles
Morsch, R., Simon, W., & Coleman, P. D. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199902000-00008 · Cited by 370
Luppi, P., Aston‐Jones, G., Akaoka, H., Chouvet, G., & Jouvet, M. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00481-j · Cited by 344
Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
Irwin, D. J., Cairns, N. J., Grossman, M., McMillan, C. T., Lee, E. B., Deerlin, V. M. V., Lee, V. M. ‐., & Trojanowski, J. Q. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1380-1 · Cited by 278
Self-citationBoluda, S., Iba, M., Zhang, B., Raible, K. M., Lee, V. M. ‐., & Trojanowski, J. Q. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1373-0 · Cited by 268
Self-citationHurtado, D. E., Molina-Porcel, L., Iba, M., Aboagye, A. K., Paul, S. M., Trojanowski, J. Q., & Lee, V. M.-Y. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100346 · Cited by 222
Self-citationPeeraer, E., Bottelbergs, A., Van Kolen, K., Stancu, I.-C., Vasconcelos, B., Mahieu, M., Duytschaever, H., Ver Donck, L., Torremans, A., Sluydts, E., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.032 · Cited by 214
Self-citationNeurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo
Kuchibhotla, K. V., Wegmann, S., Kopeikina, K. J., Hawkes, J., Rudinskiy, N., Andermann, M. L., Spires-Jones, T. L., Bacskai, B. J., & Hyman, B. T. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318807111 · Cited by 193
Stancu, I.-C., Vasconcelos, B., Ris, L., Wang, P., Villers, A., Peeraer, E., Buist, A., Terwel, D., Baatsen, P., Oyelami, T., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1413-4 · Cited by 143
Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau
Van der Jeugd, A., Hochgräfe, K., Ahmed, T., Decker, J. M., Sydow, A., Hofmann, A., Wu, D., Messing, L., Balschun, D., D’Hooge, R., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0987-3 · Cited by 135
Guo, J., & Lee, V. M. ‐. (2013) · FEBS Letters · doi:10.1016/j.febslet.2013.01.051 · Cited by 117
Self-citationRaphe projections to the locus coeruleus in the rat
Morgane, P. J., & Jacobs, M. S. (1979) · Brain Research Bulletin · doi:10.1016/0361-9230(79)90037-6 · Cited by 115
Morozova, O. A., March, Z. M., Robinson, A. S., & Colby, D. W. (2013) · Biochemistry · doi:10.1021/bi400866w · Cited by 92
Clavier, R. M. (1979) · Brain Research Bulletin · doi:10.1016/0361-9230(79)90034-0 · Cited by 59
Detection of d-aspartate in tau proteins associated with Alzheimer paired helical filaments
Kenessey, Á., Yen, S.-H. C., Liu, W.-K., Yang, X.-R., & Dunlop, D. S. (1995) · Brain Research · doi:10.1016/0006-8993(95)00061-t · Cited by 39
Duration of neurofibrillary changes in the hippocampal pyramidal neurons
Bobinski, M., Węgiel, J., Tarnawski, M. J., Bobinski, M., de Leon, M. J., Reisberg, ., Miller, D. C., & Wı́sniewski, H. M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00441-7 · Cited by 38
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Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565
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Metadata
- Authors
- Iba, M., McBride, J. D., Guo, J. L., Zhang, B., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- Acta Neuropathologica
- Published
- 2015-07-07
- Volume
- 130
- Issue
- 3
- Pages
- 349-362
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4545685
- OpenAlex
- W812488793
- Cited by
- 223
- References
- 46
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 17 · 2023: 15 · 2022: 20 · 2021: 22 · 2020: 32 · 2019: 26 · 2018: 23 · 2017: 24 · 2016: 16 · 2015: 2
- FWCI
- 15.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health Grant (AG17586)
- the Marian S. Ware Alzheimer Program Cure Alzheimer’s Fund
- the Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund
- the Paula C. Schmerler Fund for Alzheimer’s Research
- the Barrist Neurodegenerative Disease Research Fund
- the Eleanor Margaret Kurtz Endowed Fund
- the Mary Rasmus Endowed Fund for Alzheimer’s Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cell-to-cell transmission, locus coeruleus, PS19 mice, P301S tau, Alzheimer's disease, Braak hypothesis, tau tangles, efferent projections, axon terminals, neuronal perikarya, neurodegeneration
- MeSH terms
- Afferent Pathways, Animals, Disease Models, Animal, Efferent Pathways, Escherichia coli, Female, Humans, Hypothalamus, Immunohistochemistry, Locus Coeruleus, Male, Mice, Transgenic, Mutation, Neurons, Thalamus, Tyrosine 3-Monooxygenase, tau Proteins, Disease Progression, Tauopathies
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