{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:57:05Z","timestamp":1787003825445,"version":"build-2736575974"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T00:00:00Z","timestamp":1487894400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T00:00:00Z","timestamp":1487894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer\u2019s disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene\n                    <jats:italic>MAPT<\/jats:italic>\n                    cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human\n                    <jats:italic>MAPT<\/jats:italic>\n                    locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous\n                    <jats:italic>Mapt<\/jats:italic>\n                    \u2212\/\u2212 background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.\n                  <\/jats:p>","DOI":"10.1038\/srep43198","type":"journal-article","created":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T06:20:13Z","timestamp":1487917213000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy"],"prefix":"10.1038","volume":"7","author":[{"given":"Heike J.","family":"Wobst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Denk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Oliver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achilleas","family":"Livieratos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonya N.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria H.","family":"Knudsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Bengoa-Vergniory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bannerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wade-Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,24]]},"reference":[{"key":"BFsrep43198_CR1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0304-3940(99)00303-1","volume":"266","author":"F Crawford","year":"1999","unstructured":"Crawford, F. et al. No genetic association between polymorphisms in the Tau gene and Alzheimer\u2019s disease in clinic or population based samples. Neurosci. Lett. 266, 193\u2013196 (1999).","journal-title":"Neurosci. Lett."},{"key":"BFsrep43198_CR2","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1093\/hmg\/ddi241","volume":"14","author":"AJ Myers","year":"2005","unstructured":"Myers, A. J. et al. The H1c haplotype at the MAPT locus is associated with Alzheimer\u2019s disease. Hum. Mol. Genet. 14, 2399\u20132404 (2005).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep43198_CR3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0304-3940(00)01057-0","volume":"285","author":"M Baker","year":"2000","unstructured":"Baker, M. et al. No association between TAU haplotype and Alzheimer\u2019s disease in population or clinic based series or in familial disease. Neurosci. Lett. 285, 147\u2013149 (2000).","journal-title":"Neurosci. Lett."},{"key":"BFsrep43198_CR4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/S0304-3940(01)02289-3","volume":"314","author":"C Russ","year":"2001","unstructured":"Russ, C. et al. The microtubule associated protein Tau gene and Alzheimer\u2019s disease\u2013an association study and meta-analysis. Neurosci. Lett. 314, 92\u201396 (2001).","journal-title":"Neurosci. Lett."},{"key":"BFsrep43198_CR5","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1002\/ajmg.b.30951","volume":"150B","author":"R Abraham","year":"2009","unstructured":"Abraham, R. et al. An association study of common variation at the MAPT locus with late-onset Alzheimer\u2019s disease. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet. 150B, 1152\u20131155 (2009).","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet. Off. Publ. Int. Soc. Psychiatr. Genet."},{"key":"BFsrep43198_CR6","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1093\/hmg\/7.11.1825","volume":"7","author":"C Dumanchin","year":"1998","unstructured":"Dumanchin, C. et al. Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum. Mol. Genet. 7, 1825\u20131829 (1998).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep43198_CR7","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/31508","volume":"393","author":"M Hutton","year":"1998","unstructured":"Hutton, M. et al. Association of missense and 5\u2032-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702\u2013705 (1998).","journal-title":"Nature"},{"key":"BFsrep43198_CR8","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/ana.410430617","volume":"43","author":"P Poorkaj","year":"1998","unstructured":"Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815\u2013825 (1998).","journal-title":"Ann. Neurol."},{"key":"BFsrep43198_CR9","doi-asserted-by":"crossref","first-page":"7737","DOI":"10.1073\/pnas.95.13.7737","volume":"95","author":"MG Spillantini","year":"1998","unstructured":"Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737\u20137741 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep43198_CR10","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1093\/hmg\/ddl429","volume":"15","author":"TM Caffrey","year":"2006","unstructured":"Caffrey, T. M., Joachim, C., Paracchini, S., Esiri, M. M. & Wade-Martins, R. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15, 3529\u20133537 (2006).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep43198_CR11","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.neurobiolaging.2007.05.002","volume":"29","author":"TM Caffrey","year":"2008","unstructured":"Caffrey, T. M., Joachim, C. & Wade-Martins, R. Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol. Aging 29, 1923\u20131929 (2008).","journal-title":"Neurobiol. Aging"},{"key":"BFsrep43198_CR12","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nrneurol.2012.169","volume":"8","author":"R Wade-Martins","year":"2012","unstructured":"Wade-Martins, R. Genetics: The MAPT locus-a genetic paradigm in disease susceptibility. Nat. Rev. Neurol. 8, 477\u2013478 (2012).","journal-title":"Nat. Rev. Neurol."},{"key":"BFsrep43198_CR13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2007.04.006","volume":"27","author":"TM Caffrey","year":"2007","unstructured":"Caffrey, T. M. & Wade-Martins, R. Functional MAPT haplotypes: bridging the gap between genotype and neuropathology. Neurobiol. Dis. 27, 1\u201310 (2007).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep43198_CR14","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/1531-8249(200002)47:2<242::AID-ANA16>3.0.CO;2-L","volume":"47","author":"P Pastor","year":"2000","unstructured":"Pastor, P. et al. Significant association between the tau gene A0\/A0 genotype and Parkinson\u2019s disease. Ann. Neurol. 47, 242\u2013245 (2000).","journal-title":"Ann. Neurol."},{"key":"BFsrep43198_CR15","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1136\/jnnp.2003.026203","volume":"75","author":"DG Healy","year":"2004","unstructured":"Healy, D. G. et al. Tau gene and Parkinson\u2019s disease: a case-control study and meta-analysis. J. Neurol. Neurosurg. Psychiatry 75, 962\u2013965 (2004).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"BFsrep43198_CR16","first-page":"223","volume":"24","author":"M Zappia","year":"2003","unstructured":"Zappia, M. et al. Association of tau gene polymorphism with Parkinson\u2019s disease. Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 24, 223\u2013224 (2003).","journal-title":"Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol."},{"key":"BFsrep43198_CR17","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/ng.487","volume":"41","author":"J Sim\u00f3n-S\u00e1nchez","year":"2009","unstructured":"Sim\u00f3n-S\u00e1nchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson\u2019s disease. Nat. Genet. 41, 1308\u20131312 (2009).","journal-title":"Nat. Genet."},{"key":"BFsrep43198_CR18","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1469-1809.2009.00560.x","volume":"74","author":"TL Edwards","year":"2010","unstructured":"Edwards, T. L. et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74, 97\u2013109 (2010).","journal-title":"Ann. Hum. Genet."},{"key":"BFsrep43198_CR19","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nm.3617","volume":"20","author":"M Fern\u00e1ndez-Nogales","year":"2014","unstructured":"Fern\u00e1ndez-Nogales, M. et al. Huntington\u2019s disease is a four-repeat tauopathy with tau nuclear rods. Nat. Med. 20, 881\u2013885 (2014).","journal-title":"Nat. Med."},{"key":"BFsrep43198_CR20","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0022-2836(77)90214-5","volume":"116","author":"DW Cleveland","year":"1977","unstructured":"Cleveland, D. W., Hwo, S. Y. & Kirschner, M. W. Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J. Mol. Biol. 116, 227\u2013247 (1977).","journal-title":"J. Mol. Biol."},{"key":"BFsrep43198_CR21","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0022-2836(77)90213-3","volume":"116","author":"DW Cleveland","year":"1977","unstructured":"Cleveland, D. W., Hwo, S. Y. & Kirschner, M. W. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207\u2013225 (1977).","journal-title":"J. Mol. Biol."},{"key":"BFsrep43198_CR22","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0022-2836(77)90021-3","volume":"117","author":"DB Murphy","year":"1977","unstructured":"Murphy, D. B., Johnson, K. A. & Borisy, G. G. Role of tubulin-associated proteins in microtubule nucleation and elongation. J. Mol. Biol. 117, 33\u201352 (1977).","journal-title":"J. Mol. Biol."},{"key":"BFsrep43198_CR23","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1073\/pnas.72.5.1858","volume":"72","author":"MD Weingarten","year":"1975","unstructured":"Weingarten, M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 72, 1858\u20131862 (1975).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep43198_CR24","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1093\/emboj\/cdf503","volume":"21","author":"A Seitz","year":"2002","unstructured":"Seitz, A. et al. Single-molecule investigation of the interference between kinesin, tau and MAP2c. EMBO J. 21, 4896\u20134905 (2002).","journal-title":"EMBO J"},{"key":"BFsrep43198_CR25","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1073\/pnas.0607919104","volume":"104","author":"M Vershinin","year":"2007","unstructured":"Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J. & Gross, S. P. Multiple-motor based transport and its regulation by Tau. Proc. Natl. Acad. Sci. USA 104, 87\u201392 (2007).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep43198_CR26","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1523\/JNEUROSCI.16-18-05583.1996","volume":"16","author":"M Kempf","year":"1996","unstructured":"Kempf, M., Clement, A., Faissner, A., Lee, G. & Brandt, R. Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J. Neurosci. Off. J. Soc. Neurosci. 16, 5583\u20135592 (1996).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep43198_CR27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cell.2010.06.036","volume":"142","author":"LM Ittner","year":"2010","unstructured":"Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer\u2019s disease mouse models. Cell 142, 387\u2013397 (2010).","journal-title":"Cell"},{"key":"BFsrep43198_CR28","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/0896-6273(89)90210-9","volume":"3","author":"M Goedert","year":"1989","unstructured":"Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer\u2019s disease. Neuron 3, 519\u2013526 (1989).","journal-title":"Neuron"},{"key":"BFsrep43198_CR29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neurobiolaging.2007.05.010","volume":"30","author":"F Denk","year":"2009","unstructured":"Denk, F. & Wade-Martins, R. Knock-out and transgenic mouse models of tauopathies. Neurobiol. Aging 30, 1\u201313 (2009).","journal-title":"Neurobiol. Aging"},{"key":"BFsrep43198_CR30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s004010000333","volume":"102","author":"E Iseki","year":"2001","unstructured":"Iseki, E. et al. Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells. Acta Neuropathol. (Berl.) 102, 285\u2013292 (2001).","journal-title":"Acta Neuropathol. (Berl.)"},{"key":"BFsrep43198_CR31","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0304-3940(02)00124-6","volume":"323","author":"A Grover","year":"2002","unstructured":"Grover, A., DeTure, M., Yen, S. H. & Hutton, M. Effects on splicing and protein function of three mutations in codon N296 of tau in vitro . Neurosci. Lett. 323, 33\u201336 (2002).","journal-title":"Neurosci. Lett."},{"key":"BFsrep43198_CR32","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1046\/j.0022-3042.2001.00729.x","volume":"80","author":"H Yoshida","year":"2002","unstructured":"Yoshida, H., Crowther, R. A. & Goedert, M. Functional effects of tau gene mutations deltaN296 and N296H. J. Neurochem. 80, 548\u2013551 (2002).","journal-title":"J. Neurochem."},{"key":"BFsrep43198_CR33","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1074\/jbc.M409876200","volume":"280","author":"D Terwel","year":"2005","unstructured":"Terwel, D. et al. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R\/2N transgenic mice. J. Biol. Chem. 280, 3963\u20133973 (2005).","journal-title":"J. Biol. Chem."},{"key":"BFsrep43198_CR34","doi-asserted-by":"crossref","first-page":"5704","DOI":"10.1016\/j.febslet.2005.09.047","volume":"579","author":"T Taniguchi","year":"2005","unstructured":"Taniguchi, T. et al. Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibrillary tangle formation. FEBS Lett. 579, 5704\u20135712 (2005).","journal-title":"FEBS Lett."},{"key":"BFsrep43198_CR35","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1126\/science.1113694","volume":"309","author":"K Santacruz","year":"2005","unstructured":"Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476\u2013481 (2005).","journal-title":"Science"},{"key":"BFsrep43198_CR36","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1242\/jcs.114.6.1179","volume":"114","author":"HN Dawson","year":"2001","unstructured":"Dawson, H. N. et al. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J. Cell Sci. 114, 1179\u20131187 (2001).","journal-title":"J. Cell Sci."},{"key":"BFsrep43198_CR37","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/mt.2009.64","volume":"17","author":"PP Peruzzi","year":"2009","unstructured":"Peruzzi, P. P. et al. Physiological transgene regulation and functional complementation of a neurological disease gene deficiency in neurons. Mol. Ther. J. Am. Soc. Gene Ther. 17, 1517\u20131526 (2009).","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"BFsrep43198_CR38","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00335-001-2128-5","volume":"13","author":"LS Kulnane","year":"2002","unstructured":"Kulnane, L. S., Lehman, E. J. H., Hock, B. J., Tsuchiya, K. D. & Lamb, B. T. Rapid and efficient detection of transgene homozygosity by FISH of mouse fibroblasts. Mamm. Genome Off. J. Int. Mamm. Genome Soc. 13, 223\u2013226 (2002).","journal-title":"Mamm. Genome Off. J. Int. Mamm. Genome Soc."},{"key":"BFsrep43198_CR39","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/978-1-60761-789-1_32","volume":"659","author":"A Jefferson","year":"2010","unstructured":"Jefferson, A. & Volpi, E. V. Fluorescence in situ hybridization (FISH) for genomic investigations in rat. Methods Mol. Biol. Clifton NJ 659, 409\u2013426 (2010).","journal-title":"Methods Mol. Biol. Clifton NJ"},{"key":"BFsrep43198_CR40","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1038\/nprot.2007.153","volume":"2","author":"G Obernosterer","year":"2007","unstructured":"Obernosterer, G., Martinez, J. & Alenius, M. Locked nucleic acid-based in situ detection of microRNAs in mouse tissue sections. Nat. Protoc. 2, 1508\u20131514 (2007).","journal-title":"Nat. Protoc."},{"key":"BFsrep43198_CR41","doi-asserted-by":"crossref","first-page":"4022","DOI":"10.1093\/hmg\/ddp346","volume":"18","author":"J Alegre-Abarrategui","year":"2009","unstructured":"Alegre-Abarrategui, J. et al. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum. Mol. Genet. 18, 4022\u20134034 (2009).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep43198_CR42","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1046\/j.1471-4159.2003.01879.x","volume":"86","author":"C Andorfer","year":"2003","unstructured":"Andorfer, C. et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582\u2013590 (2003).","journal-title":"J. Neurochem."},{"key":"BFsrep43198_CR43","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1006\/nbdi.1999.0279","volume":"7","author":"K Duff","year":"2000","unstructured":"Duff, K. et al. Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol. Dis. 7, 87\u201398 (2000).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep43198_CR44","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1002\/j.1460-2075.1992.tb05204.x","volume":"11","author":"J Biernat","year":"1992","unstructured":"Biernat, J. et al. The switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region. EMBO J. 11, 1593\u20131597 (1992).","journal-title":"EMBO J."},{"key":"BFsrep43198_CR45","doi-asserted-by":"crossref","first-page":"9340","DOI":"10.1523\/JNEUROSCI.22-21-09340.2002","volume":"22","author":"B Allen","year":"2002","unstructured":"Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. Off. J. Soc. Neurosci. 22, 9340\u20139351 (2002).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep43198_CR46","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/0006-8993(89)91396-6","volume":"477","author":"C Bancher","year":"1989","unstructured":"Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer\u2019s disease. Brain Res. 477, 90\u201399 (1989).","journal-title":"Brain Res."},{"key":"BFsrep43198_CR47","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0002-9440(10)65272-8","volume":"154","author":"JP Brion","year":"1999","unstructured":"Brion, J. P., Tremp, G. & Octave, J. N. Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer\u2019s disease. Am. J. Pathol. 154, 255\u2013270 (1999).","journal-title":"Am. J. Pathol."},{"key":"BFsrep43198_CR48","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1002\/j.1460-2075.1995.tb07116.x","volume":"14","author":"J G\u00f6tz","year":"1995","unstructured":"G\u00f6tz, J. et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J. 14, 1304\u20131313 (1995).","journal-title":"EMBO J."},{"key":"BFsrep43198_CR49","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/78078","volume":"25","author":"J Lewis","year":"2000","unstructured":"Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402\u2013405 (2000).","journal-title":"Nat. Genet."},{"key":"BFsrep43198_CR50","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1006\/mcne.2001.1051","volume":"18","author":"F Lim","year":"2001","unstructured":"Lim, F. et al. FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol. Cell. Neurosci. 18, 702\u2013714 (2001).","journal-title":"Mol. Cell. Neurosci."},{"key":"BFsrep43198_CR51","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bbadis.2004.08.009","volume":"1739","author":"I D\u2019Souza","year":"2005","unstructured":"D\u2019Souza, I. & Schellenberg, G. D. Regulation of tau isoform expression and dementia. Biochim. Biophys. Acta 1739, 104\u2013115 (2005).","journal-title":"Biochim. Biophys. Acta"},{"key":"BFsrep43198_CR52","doi-asserted-by":"crossref","first-page":"1922.e7","DOI":"10.1016\/j.neurobiolaging.2013.01.017","volume":"34","author":"E Majounie","year":"2013","unstructured":"Majounie, E. et al. Variation in tau isoform expression in different brain regions and disease states. Neurobiol. Aging 34, 1922.e7\u20131922.e12 (2013).","journal-title":"Neurobiol. Aging"},{"key":"BFsrep43198_CR53","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0165-3806(03)00056-7","volume":"142","author":"H Takuma","year":"2003","unstructured":"Takuma, H., Arawaka, S. & Mori, H. Isoforms changes of tau protein during development in various species. Brain Res. Dev. Brain Res. 142, 121\u2013127 (2003).","journal-title":"Brain Res. Dev. Brain Res."},{"key":"BFsrep43198_CR54","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1093\/hmg\/dds238","volume":"21","author":"D Trabzuni","year":"2012","unstructured":"Trabzuni, D. et al. MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum. Mol. Genet. 21, 4094\u20134103 (2012).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep43198_CR55","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1002\/j.1460-2075.1990.tb07870.x","volume":"9","author":"M Goedert","year":"1990","unstructured":"Goedert, M. & Jakes, R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 9, 4225\u20134230 (1990).","journal-title":"EMBO J."},{"key":"BFsrep43198_CR56","doi-asserted-by":"crossref","first-page":"5446","DOI":"10.1523\/JNEUROSCI.4637-04.2005","volume":"25","author":"C Andorfer","year":"2005","unstructured":"Andorfer, C. et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. Off. J. Soc. Neurosci. 25, 5446\u20135454 (2005).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep43198_CR57","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1002\/cne.21867","volume":"511","author":"P McMillan","year":"2008","unstructured":"McMillan, P. et al. Tau isoform regulation is region- and cell-specific in mouse brain. J. Comp. Neurol. 511, 788\u2013803 (2008).","journal-title":"J. Comp. Neurol."},{"key":"BFsrep43198_CR58","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.neurobiolaging.2009.06.007","volume":"32","author":"M Hundelt","year":"2011","unstructured":"Hundelt, M. et al. Altered phosphorylation but no neurodegeneration in a mouse model of tau hyperphosphorylation. Neurobiol. Aging 32, 991\u20131006 (2011).","journal-title":"Neurobiol. Aging"},{"key":"BFsrep43198_CR59","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1006\/nbdi.2001.0439","volume":"8","author":"K Tanemura","year":"2001","unstructured":"Tanemura, K. et al. Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol. Dis. 8, 1036\u20131045 (2001).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep43198_CR60","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0304-3940(99)00964-7","volume":"279","author":"S Ikegami","year":"2000","unstructured":"Ikegami, S., Harada, A. & Hirokawa, N. Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci. Lett. 279, 129\u2013132 (2000).","journal-title":"Neurosci. Lett."},{"key":"BFsrep43198_CR61","doi-asserted-by":"crossref","first-page":"599","DOI":"10.2353\/ajpath.2006.060002","volume":"169","author":"K Schindowski","year":"2006","unstructured":"Schindowski, K. et al. Alzheimer\u2019s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am. J. Pathol. 169, 599\u2013616 (2006).","journal-title":"Am. J. Pathol."},{"key":"BFsrep43198_CR62","doi-asserted-by":"crossref","first-page":"13896","DOI":"10.1073\/pnas.202205599","volume":"99","author":"Y Tatebayashi","year":"2002","unstructured":"Tatebayashi, Y. et al. Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc. Natl. Acad. Sci. USA 99, 13896\u201313901 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep43198_CR63","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S0006-3223(00)01028-3","volume":"49","author":"X Liu","year":"2001","unstructured":"Liu, X. & Gershenfeld, H. K. Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice. Biol. Psychiatry 49, 575\u2013581 (2001).","journal-title":"Biol. Psychiatry"},{"key":"BFsrep43198_CR64","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.brainres.2005.08.004","volume":"1059","author":"N Egashira","year":"2005","unstructured":"Egashira, N. et al. Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice. Brain Res. 1059, 7\u201312 (2005).","journal-title":"Brain Res."},{"key":"BFsrep43198_CR65","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.neuroscience.2011.08.057","volume":"196","author":"M Llorens-Martin","year":"2011","unstructured":"Llorens-Martin, M., Hernandez, F. & Avila, J. Expression of frontotemporal dementia with parkinsonism associated to chromosome 17 tau induces specific degeneration of the ventral dentate gyrus and depressive-like behavior in mice. Neuroscience 196, 215\u2013227 (2011).","journal-title":"Neuroscience"},{"key":"BFsrep43198_CR66","doi-asserted-by":"crossref","first-page":"9155","DOI":"10.1523\/JNEUROSCI.5492-06.2007","volume":"27","author":"HN Dawson","year":"2007","unstructured":"Dawson, H. N., Cantillana, V., Chen, L. & Vitek, M. P. The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. J. Neurosci. Off. J. Soc. Neurosci. 27, 9155\u20139168 (2007).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep43198_CR67","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.neuron.2016.04.042","volume":"90","author":"KM Schoch","year":"2016","unstructured":"Schoch, K. M. et al. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron 90, 941\u2013947 (2016).","journal-title":"Neuron"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep43198.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep43198","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep43198.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T20:20:55Z","timestamp":1671826855000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep43198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,24]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,3,9]]}},"alternative-id":["BFsrep43198"],"URL":"https:\/\/doi.org\/10.1038\/srep43198","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,24]]},"assertion":[{"value":"1 June 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 January 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"43198"}}