Tangle-Bearing Neurons Survive Despite Disruption of Membrane Integrity in a Mouse Model of Tauopathy
Open accessAbstract
Neurofibrillary tangles (NFTs) are associated with neuronal loss and correlate with cognitive impairment in Alzheimer disease, but how NFTs relate to neuronal death is not clear. We studied cell death in Tg4510 mice that reversibly express P301L mutant human tau and accumulate NFTs using in vivo multiphoton imaging of neurofibrillary pathology, propidium iodide (PI) incorporation into cells, caspase activation, and DNA labeling. We first observed that in live mice, a minority of neurons were labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die during a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption, as suggested by PI staining, and caspase activation do not lead to immediate death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathological alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology.
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?
NFT-containing neurons can survive for decades, indicating that NFTs are neither obligatory nor sufficient to induce neuronal dysfunction and toxicity.
“NFT‐containing neurons can survive for decades, 7 , 8 indicating that NFTs are neither obligatory nor sufficient to induce neuronal dysfunction and toxicity.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [7]
Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways have been implicated as consequences of tau mislocalization or oligomerization.
“Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways (including caspase activation and inflammatory responses) have all been directly or indirectly implicated as consequences of tau mislocalization or oligomerization (20, 40, 43–52).”
From All the Tau We Cannot See (2023) · cites this paper as [44]
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
Tau 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 · see citing works
Self-citationBuée, L., Bussière, T., Buée‐Scherrer, V., Delacourte, A., & Hof, P. R. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00019-9 · Cited by 2,007 · see citing works
Ramsden, M., Kotilinek, L., Forster, C., Paulson, J., McGowan, E., SantaCruz, K., Guimaraes, A., Yue, M., Lewis, J., Carlson, G., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3279-05.2005 · Cited by 702 · see citing works
Self-citationIRIZARRY, M. C., MCNAMARA, M., FEDORCHAK, K., HSIAO, K., & HYMAN, B. T. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199709000-00002 · Cited by 649 · see citing works
Self-citationSpires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 1× · see citing works
“In vivo imaging was performed using a Bio-Rad 1024ES multiphoton microscope (Bio-Rad Laboratories, Hercules, CA) with 800-nm excitation (Ti:Sapphire laser; Mai Tai, Spectra-Physics, Mountain View, CA) for thioflavin S, as previously described (10).”
Self-citationSpires, T. L., Orne, J. D., SantaCruz, K., Pitstick, R., Carlson, G. A., Ashe, K. H., & Hyman, B. T. (2006) · The American Journal of Pathology · doi:10.2353/ajpath.2006.050840 · Cited by 401 · see citing works
Self-citationLimits of propidium iodide as a cell viability indicator for environmental bacteria
Shi, L., Günther, S., Hübschmann, T., et al. (2007) · Cytometry Part A · doi:10.1002/cyto.a.20402 · Cited by 275 · see citing works
Chapter 16 Fluorescence Labeling and Microscopy of DNA
Arndt‐Jovin, D. J., & Jovin, T. M. (1989) · Methods in cell biology · doi:10.1016/s0091-679x(08)60989-9 · Cited by 198 · see citing works
Trojanowski, J. Q., & LEE, V. M. ‐. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05561.x · Cited by 184 · see citing works
Spires-Jones, T. L., de Calignon, A., Matsui, T., Zehr, C., Pitstick, R., Wu, H.-Y., Osetek, J. D., Jones, P. B., Bacskai, B. J., Feany, M. B., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3072-08.2008 · Cited by 137 · see citing works
Self-citationUnal Cevik, I., & Dalkara, T. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401250 · Cited by 114 · see citing works
Stereology: A Practical Primer for Neuropathology
Hyman, B. T., Gómez‐Isla, T., & Irizarry, M. C. (1998) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199804000-00001 · Cited by 84 · see citing works
Self-citationMcLaughlin, B. (2004) · APOPTOSIS · doi:10.1023/b:appt.0000018793.10779.dc · Cited by 80 · see citing works
In Vivo Imaging of Amyloid-β Deposits in Mouse Brain With Multiphoton Microscopy
Skoch, J. M., Hickey, G. A., Kajdasz, S. T., Hyman, B. T., & Bacskai, B. J. (2005) · Humana Press eBooks · doi:10.1385/1-59259-874-9:349 · Cited by 45 · see citing works
Self-citationPropidium iodide in vivo: an early marker of neuronal damage in rat hippocampus
Wilde, G. J. C., Sundström, L., & Iannotti, F. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90525-8 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neuropathological alterations in Alzheimer disease
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006189 · Cited by 3,345 · see citing works
Self-citationRoles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Morris, M., Maeda, S., Vossel, K., & Mucke, L. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.009 · Cited by 899 · see citing works
Tau protein aggregation is associated with cellular senescence in the brain
Musi, N., Valentine, J. M., Sickora, K. R., Baeuerle, E., Thompson, C. S., Shen, Q., & Orr, M. E. (2018) · Aging Cell · doi:10.1111/acel.12840 · Cited by 595 · see citing works
Caspase activation precedes and leads to tangles
de Calignon, A., Fox, L. M., Pitstick, R., Carlson, G. A., Bacskai, B. J., Spires-Jones, T. L., & Hyman, B. T. (2010) · Nature · doi:10.1038/nature08890 · Cited by 517 · see citing works
Self-citationMicroglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., & Holtzman, D. M. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190980 · Cited by 448 · see citing works
Cellular senescence in brain aging
Sikora, E., Bielak-Zmijewska, A., Dudkowska, M., Krzystyniak, A., Mosieniak, G., Wesierska, M., & Wlodarczyk, J. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.646924 · Cited by 304 · see citing works
“In response to an acute injury, there is an increase in reactive astrocytes: cells undergo various alterations including swelling, hypertrophy, proliferation, and increased expression of a cytoskeletal protein, GFAP (Verkhratsky et al., 2010).”
BackgroundInfluentialCellular senescence and Alzheimer disease: the egg and the chicken scenario
Saez-Atienzar, S., & Masliah, E. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-020-0325-z · Cited by 257 · 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
Self-citationGaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117 · see citing works
Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease
Taddei, R. N., Perbet, R., Mate de Gerando, A., Wiedmer, A. E., Sanchez-Mico, M., Connors Stewart, T., Gaona, A., Melloni, A., Amaral, A. C., Duff, K., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.3530 · Cited by 110 · see citing works
Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes
Gómez-Isla, T., & Frosch, M. P. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00642-9 · Cited by 96 · see citing works
Puangmalai, N., Sengupta, U., Bhatt, N., Gaikwad, S., Montalbano, M., Bhuyan, A., Garcia, S., McAllen, S., Sonawane, M., Jerez, C., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101766 · Cited by 68 · see citing works
Means, J. C., Gerdes, B. C., Kaja, S., Sumien, N., Payne, A. J., Stark, D. A., Borden, P. K., Price, J. L., & Koulen, P. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1942-9 · Cited by 54 · see citing works
Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium
Seripa, D., Solfrizzi, V., Imbimbo, B. P., Daniele, A., Santamato, A., Lozupone, M., Zuliani, G., Greco, A., Logroscino, G., & Panza, F. (2016) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2016.1140039 · Cited by 50 · see citing works
Further understanding of tau phosphorylation: implications for therapy
Medina, M., & Avila, J. (2015) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2015.1000864 · Cited by 41 · see citing works
Hyman, B. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-042921-023749 · Cited by 39 · see citing works
Self-citationSome evolutionary perspectives on Alzheimer's disease pathogenesis and pathology
Glass, D. J., & Arnold, S. E. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.05.2408 · Cited by 29 · see citing works
Spires-Jones, T. L., Calignon, A. D., Meyer-Luehmann, M., Bacskai, B. J., & Hyman, B. T. (2011) · Methods · doi:10.1016/j.ymeth.2010.12.009 · Cited by 24 · see citing works
Self-citation
- Authors
- de Calignon, A., Spires-Jones, T. L., Pitstick, R., Carlson, G. A., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-07
- Volume
- 68
- Issue
- 7
- Pages
- 757-761
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC2756569
- OpenAlex
- W2095860147
- Cited by
- 81
- References
- 15
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (AG08487)
- National Institute on Aging (AG-08487, R01AG026249, R01AG008487, AG026249, P50AG005134, K99AG033670, P30AG062421)
- 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
- neurofibrillary tangles, tauopathy, neuronal survival, neuronal cell death, P301L tau, membrane integrity disruption, caspase activation, propidium iodide staining, Alzheimer's disease
- MeSH terms
- Animals, Brain, Cell Membrane, Cell Survival, Disease Models, Animal, Fluorescence, Mice, Transgenic, Nerve Degeneration, Neurons, Propidium, Stress, Physiological, Time Factors, Neurofibrillary Tangles, tau Proteins, Cell Death, Caspases, Tauopathies, Microscopy, Fluorescence, Multiphoton, 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
