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Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms
Open accessAbstract
Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.
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“However, neuronal loss appears to be independent of tangle formation in some transgenic mouse models (12)(13)(14).”
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Liebscher, S., & Meyer‐Luehmann, M. (2012) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2012.00026 · Cited by 36
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Wısnıewskı, T., & Boutajangout, A. (2009) · Brain Structure and Function · doi:10.1007/s00429-009-0236-2 · Cited by 39
“…did not develop NFTs, with the exception of two models: One expressing ON3R wild-type tau with a few NFTs in aged animals (Ishihara et al. 2001) and another with abundant NFTs that expresses all six human tau iso- forms on a knockout background for murine tau (Andorfer et al. 2003, 2005).”
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“This transgenic mouse line was generated by crossing TghTau mice (39) with a mouse model that expresses the PS1 M146L human mutation (40).”
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“Several previous studies have established that HTau mice exhibit age-related hyperphosphorylation and aggregation of MAPT (Andorfer et al., 2003), accumulation of NFTs and displayed significant neuronal cell death (Andorfer et al., 2005).”
BackgroundResultLineage-Specific Regulation of Epigenetic Modifier Genes in Human Liver and Brain
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“This effect of tau45-230 on neuronal survival is consistent with reports showing that overexpression of tau isoforms is associated with neuronal loss in other brain areas (Andorfer et al., 2005).”
BackgroundResultZinc Binding to Tau Influences Aggregation Kinetics and Oligomer Distribution
Moreira, G. G., Cristóvão, J. S., Torres, V. M., Carapeto, A. P., Rodrigues, M. S., Landrieu, I., CORDEIRO, C. A., & Gomes, C. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20235979 · Cited by 44
“These species and/or the on-pathway species are cytotoxic and they lead to neuronal death [3].”
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Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro
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A Tangled Web – Tau and Sporadic Parkinson's Disease
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“In a transgenic mouse model overexpressing non-mutant, human tau, the presence of tau filaments did not correlate with cell death (Andorfer et al., 2005).”
BackgroundRole of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution
Vergara, C., Ordóñez‐Gutiérrez, L., Wandosell, F. G., Ferrer, I., del Rı́o, J. A., & Gavı́n, R. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8793-7 · Cited by 38
“It has been reported that the single overexpression of human tau in a mouse model is robust enough to induce tau phosphorylation [88] and neuronal aggregation [89].”
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“Even though an immediate cause of cell death in degenerating neurons has not been proved, the increase of NFTs and/or extracellular ghost tangles (eNFTs) in the ultimate stage of the neurofibrillary pathology ( Alzheimer 1911 ) have shown parallel relation with cell loss (Bondareff et al. 1989; Braak et al. 1994; Schw…”
BackgroundModeling Tauopathy in the Fruit Fly Drosophila melanogaster
Khurana, V. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15403 · Cited by 31
“For example, ectopic expression of human wild-type tau in the mouse brain does not yield toxicity unless the genetic background is null for endogenous mouse tau [3].”
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“In order to assess the effect of HSP inhibition in vivo , transgenic mice humanized for the tau gene [5,6] were treated with a purine-scaffold HSP90 inhibitor EC102 at 200 mg/kg per day for 7 days.”
Woodhouse, A., Dickson, T., West, A., Mclean, C., & Vickers, J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.11.010 · Cited by 34
Animal models of Alzheimer’s disease: preclinical insights and challenges
Xu, Q., Yang, W., Zhong, M., Lin, Z., Gray, N. E., & Xian, Y. (2023) · Acta Materia Medica · doi:10.15212/amm-2023-0001 · Cited by 30
“Compared with the wild-type littermates, hTau mice exhibit significant deficits in spontaneous burrowing behavior at 4 months of age [76], as well as spatial learning and memory at 6-12 months of age [77, 78], with neuronal loss detected at 8-18 months of age [79].”
Gene Therapy Models of Alzheimer’s Disease and Other Dementias
Combs, B., Kneynsberg, A., & Kanaan, N. M. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-3271-9_25 · Cited by 33
“The initial transgenic mice that expressed wild-type human tau resulted in hyperphosphorylation of the protein but lacked the more mature NFT-like inclusions associated with tauopathies [75, 76].”
BackgroundTau aggregates as immunotherapeutic targets.
Castillo-Carranza, D. L., Lasagna-Reeves, C., & Kayed, R. (2013) · Frontiers in Bioscience · doi:10.2741/s381 · Cited by 33
“However, not all senescent neurons contained NFT (92, 93).”
BackgroundTransdermal Delivery of Treatment for Alzheimer’s Disease
Chan, A. L. F., Chien, Y. W., & Lin, S. J. (2008) · Drugs & Aging · doi:10.2165/00002512-200825090-00003 · Cited by 32
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“Extensive Ser(238) occupation is observed in older Htau mice, which present strong cognitive deficits and quantitative neuronal loss in their brains (39).”
BackgroundKokiko-Cochran, O. N., Saber, M., Puntambekar, S., Bemiller, S. M., Katsumoto, A., Lee, Y.-S., Bhaskar, K., Ransohoff, R. M., & Lamb, B. T. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5203 · Cited by 32
Pioglitazone prevents tau oligomerization
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Impaired burrowing is the most prominent behavioral deficit of aging htau mice
Geiszler, P. C., Barron, M. R., & Pardon, M. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.05.004 · Cited by 30
“, 2010) as well as decreasing cortical thickness from ten-months-of-age onward, and neuronal cell loss at seventeen months of age (Andorfer et al., 2005).”
Wheeler, J. M., McMillan, P. J., Hawk, M., Iba, M., Robinson, L., Xu, G. J., Dombroski, B. A., Jeong, D., Dichter, M. A., Juul, H., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0210-6 · Cited by 31
“Htau mice [28, 29] express all isoforms of human tau, but do not express any mouse 4R tau, thus producing an imbalance of 3R:4R tau.”
BackgroundZhang, Y., Song, X., & Herrup, K. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01887-5 · Cited by 33
Preparation of stable tau oligomers for cellular and biochemical studies
Karikari, T. K., Nagel, D. A., Grainger, A. I., Clarke-Bland, C., Hill, E. J., & Moffat, K. G. (2018) · Analytical Biochemistry · doi:10.1016/j.ab.2018.10.013 · Cited by 33
“Indeed, cell death and synaptic lesions have been observed independent of NFT formation [3,4], prompting a need for tau biomarkers that better correlate with disease onset and progression [5].”
BackgroundSerine racemase: a key player in apoptosis and necrosis
Canu, N., Ciotti, M. T., & Pollegioni, L. (2014) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2014.00009 · Cited by 29
“…demise (triggered by lack of survival signals or by toxic insults), which, as widely stated in this review, often implies the interplay and shift of different modes of cell death (e.g., apoptosis/necrosis or necrosis/apoptosis shift) (Jellinger, 2001; Andorfer et al., 2005; Canu et al., 2005).”
BackgroundSystemic pathology in aged mouse models of Down's syndrome and Alzheimer's disease
Levine, S., Saltzman, A., Levy, E., & Ginsberg, S. D. (2008) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2008.10.006 · Cited by 28
“Ts65Dn female carriers of translocations involving MMU 16 are mated to male C57BL/6J × C3H/HeJ F1 hybrid mice, as Ts65Dn males are subfertile (Davisson et al., 1990). Ts2 mice were generated by mating female carriers of the T(1716) 65Dn marker chromosome and Rb(12.”
Denéchaud, M., Geurs, S., Comptdaer, T., Bégard, S., García-Núñez, A., Pechereau, L.-A., Bouillet, T., Vermeiren, Y., Deyn, P. P. D., Perbet, R., et al. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102386 · Cited by 29
TOC1: A valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy
Ward, S. M., Himmelstein, D. S., Ren, Y., Fu, Y., Yu, X., Roberts, K. F., Binder, L. I., & Sahara, N. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.03.002 · Cited by 28
A Rapid Gene Delivery-Based Mouse Model for Early-Stage Alzheimer Disease-Type Tauopathy
Siman, R., Lin, Y., Malthankar‐Phatak, G. H., & Dong, Y. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000006 · Cited by 27
Thornton‐Wells, T. A., Moore, J. H., Martin, E. R., Pericak‐Vance, M. A., & Haines, J. L. (2007) · Genetic Epidemiology · doi:10.1002/gepi.20294 · Cited by 25
Alzheimer's disease and frontotemporal dementia: prospects of a tailored therapy?
Götz, J., Ittner, L. M., & Schönrock, N. (2006) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.2006.tb00615.x · Cited by 26
U1 snRNP Alteration and Neuronal Cell Cycle Reentry in Alzheimer Disease
Bai, B. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00075 · Cited by 28
“Similar cell cycle-reentry (CCR events have been extensively demonstrated and studied by several major research groups (Andorfer et al., 2005; Bauer and Patterson, 2005; Webber et al., 2005; Neve and Mcphie, 2006; Herrup and Yang, 2007; Varvel et al., 2008).”
BackgroundTatsumi, S., Uchihara, T., Aiba, I., Iwasaki, Y., Mimuro, M., Takahashi, R., & Yoshida, M. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0161-3 · Cited by 31
“Although intranuclear processes such as aberrant cell cycling may be related to the pathogenesis of AD [33,34], it is unclear how these processes are related to the perinuclear or cytoplasmic deposition of tau.”
BackgroundAhn, K.-W., Joo, Y., Choi, Y.-R., Kim, M., Lee, S. H., Cha, S., Suh, Y., & Kim, H.-S. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21690 · Cited by 27
“Microtubules are vital not only for the maintenance of cell shape but also because they play important roles in cell signaling, cell division, and mitosis (Andorfer et al., 2005).”
BackgroundJash, S., Banerjee, S., Cheng, S., Wang, B., Qiu, C., Kondo, A., Ernerudh, J., Zhou, X. Z., Lu, K. P., & Sharma, S. (2023) · Nature Communications · doi:10.1038/s41467-023-41144-6 · Cited by 26
“Female transgenic humanized tau(htau) mice expressing human Tau and lacking the endogenous mouse Tau gene (Homozygous for Mapttm1(EGFP)Klt, Hemizygous for Tg(MAPT) 8cPdav) were mated with non-carrier male (Homozygous for Maptt-m1(EGFP)Klt >, Non Carrier for Tg(MAPT)8cPdav) 40,94,95 .”
BackgroundThree‐repeat and four‐repeat tau isoforms form different oligomers
Shahpasand‐Kroner, H., Portillo, J., Lantz, C., Seidler, P. M., Sarafian, N., Loo, J. A., & Bitan, G. (2021) · Protein Science · doi:10.1002/pro.4257 · Cited by 32
Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6
Stein, D., Mizrahi, A., Golova, A., Saretzky, A., García-Venzor, A., Slobodnik, Z., Kaluski, S., Einav, M., Khrameeva, E. E., & Toiber, D. (2021) · Aging · doi:10.18632/aging.202755 · Cited by 25
Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models
Chen, Z. S., Li, L., Peng, S. I., Chen, F. M., Zhang, Q., An, Y., Lin, X., Li, W., Koon, A. C., Chan, T., et al. (2018) · EMBO Reports · doi:10.15252/embr.201745409 · Cited by 27
“In addition to polyQ diseases, apoptosis is also involved in other neurodegenerative diseases including Alzheimer’s disease (AD), Tauopathy and Parkinson’s disease (PD) [19,20].”
Overcoming translational barriers impeding development of Alzheimer's disease modifying therapies
Golde, T. E. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13583 · Cited by 29
“The hTau mice that contain a human BAC and express all of the non-mutant human tau isoforms in the context of a mouse Mapt knockout background develop limited tau pathology over long periods of time (Andorfer et al. 2005).”
BackgroundMicroRNA Landscape in Alzheimer’s Disease
Cogoni, C., Ruberti, F., & Barbato, C. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527314666150116123305 · Cited by 24
Isolation and characterization of antibody fragments selective for toxic oligomeric tau
Tian, H., Davidowitz, E. J., Lopez, P. L. D. C., He, P., Schulz, P., Moe, J. G., & Sierks, M. R. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.12.002 · Cited by 27
“…phenotypes including behavioral impairments, neuronal loss, and synapse lesions correlate better with the presence of soluble tau oligomers and prefilament species than with fibrillar NFT levels (Andorfer et al., 2005, Berger et al., 2007, Brunden et al., 2008, Polydoro et al., 2009).”
BackgroundTherapeutic and diagnostic challenges for frontotemporal dementia
Dâ€TMAlton, S., & Lewis, J. M. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00204 · Cited by 26
“Furthermore, several transgenic lines of mice and tau transgenic flies expressing various tau isoforms display a distinct dissociation between cell death and the appearance of tangle pathology (Wittmann et al., 2001; Andorfer et al., 2005; Spires et al., 2006).”
BackgroundThe Involvement of Cholinergic Neurons in the Spreading of Tau Pathology
Simón, D., Hernández, F., & Avila, J. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00074 · Cited by 25
“Also, overexpression of intracellular tau could be toxic for a cell (Andorfer et al., 2005).”
BackgroundZhao, K., Lane, G. I., Wang, L., Price, V. J., Kim, M. H., Cornwell, G. C., Fulenchek, S., Breen, G. A. M., Goux, W. J., & D’Mello, S. R. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22485 · Cited by 27
“Other studies have suggested that aggregation of tau into PHFs is not directly neurotoxic (Andorfer et al., 2005) or that formation of tau filaments protects against the neurotoxic effects of hyperphosphorylated tau (Alonso Adel et al.”
BackgroundGiliberto, L., d’Abramo, C., Acker, C. M., Davies, P., & D'adamio, L. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011609 · Cited by 25
“To this end, we have crossed our AID lines with hTau mice [29,30] overexpressing human Tau.”
BackgroundSelf-citationAging and Alzheimer’s disease connection: Nuclear Tau and lamin A
Gil, L., Niño, S. A., Capdeville, G., & Jiménez-Capdeville, M. E. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135741 · Cited by 31
Chronic Traumatic Encephalopathy: The cellular sequela to repetitive brain injury
Vile, A., & Atkinson, L. (2017) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2017.03.035 · Cited by 24
Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model
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Cholinergic neurodegeneration in Alzheimer disease mouse models
Shekari, A., & Fahnestock, M. L. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819973-2.00013-7 · Cited by 30
Friend or foe: role of pathological tau in neuronal death
Wu, M., Chen, Z., Jiang, M. H., Bao, B., Li, D., Yin, X., Wang, X., Liu, D., & Zhu, L. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02024-z · Cited by 28
“Andorfer et al. [54] provided evidence showing that in transgenic mice overexpressing human tau (htau), neurons exhibited no prominent chromatin condensation but exhibited extensive organelle swelling and cytoplasmic vacuolization suggestive of necrosis.”
hnRNP A1 Regulates Alternative Splicing of Tau Exon 10 by Targeting 3′ Splice Sites
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Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition
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Evidence of disturbed insulin signaling in animal models of Alzheimer’s disease
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Metadata
- Authors
- Andorfer, C., Acker, C. M., Kress, Y., Hof, P. R., Duff, K., & Davies, P.
- Affiliations
- Albert Einstein College of Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-06-01
- Volume
- 25
- Issue
- 22
- Pages
- 5446-5454
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725006
- OpenAlex
- W2016758992
- Cited by
- 511
- References
- 74
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 10 · 2023: 28 · 2022: 18 · 2021: 16 · 2020: 26 · 2019: 17 · 2018: 20 · 2017: 20 · 2016: 17 · 2015: 22 · 2014: 29 · 2013: 25 · 2012: 26
- FWCI
- 20.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (38623)
- National Institute on Aging (R37AG022102, AG022102, R01AG022102)
- National Institute of Mental Health (38623)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, cell cycle re-entry, neuronal cell death, neurofibrillary tangles, tauopathy, Alzheimer's disease, transgenic mice, neurodegeneration, DNA synthesis, tau filaments
- MeSH terms
- Aging, Animals, Brain, Bromodeoxyuridine, Cell Cycle, Humans, Mice, Transgenic, Nerve Degeneration, Nerve Tissue Proteins, Neurons, Neurofibrillary Tangles, tau Proteins, Cell Death, Protein Isoforms, Mice, DNA Fragmentation
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