{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:39:17Z","timestamp":1790879957825,"version":"4.1.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T00:00:00Z","timestamp":1467590400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T00:00:00Z","timestamp":1467590400000},"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":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A central question in Alzheimer\u2019s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding \u03b2-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an A\u03b2-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.<\/jats:p>","DOI":"10.1038\/ncomms12082","type":"journal-article","created":{"date-parts":[[2016,7,4]],"date-time":"2016-07-04T09:14:22Z","timestamp":1467623662000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["The neuritic plaque facilitates pathological conversion of tau in an Alzheimer\u2019s disease mouse model"],"prefix":"10.1038","volume":"7","author":[{"given":"Tong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin E.","family":"Braunstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Sibener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Deeble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip C.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,4]]},"reference":[{"key":"BFncomms12082_CR1","first-page":"77sr1","volume":"3","author":"DM Holtzman","year":"2011","unstructured":"Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer\u2019s disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr1 (2011).","journal-title":"Sci. Transl. Med."},{"key":"BFncomms12082_CR2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer\u2019s disease: progress and problems on the road to therapeutics. Science 297, 353\u2013356 (2002).","journal-title":"Science"},{"key":"BFncomms12082_CR3","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1146\/annurev.neuro.26.041002.131334","volume":"26","author":"D Selkoe","year":"2003","unstructured":"Selkoe, D. & Kopan, R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26, 565\u2013597 (2003).","journal-title":"Annu. Rev. Neurosci."},{"key":"BFncomms12082_CR4","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1146\/annurev.neuro.24.1.1121","volume":"24","author":"VM Lee","year":"2001","unstructured":"Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121\u20131159 (2001).","journal-title":"Annu. Rev. Neurosci."},{"key":"BFncomms12082_CR5","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nrn2194","volume":"8","author":"C Ballatore","year":"2007","unstructured":"Ballatore, C., Lee, V. M. Y. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer\u2019s disease and related disorders. Nat. Rev. Neurosci. 8, 663\u2013672 (2007).","journal-title":"Nat. Rev. Neurosci."},{"key":"BFncomms12082_CR6","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1038\/nrn2494","volume":"9","author":"L Bertram","year":"2008","unstructured":"Bertram, L. & Tanzi, R. E. Thirty years of Alzheimer\u2019s disease genetics: the implications of systematic meta-analyses. Nat. Rev. Neurosci. 9, 768\u2013778 (2008).","journal-title":"Nat. Rev. Neurosci."},{"key":"BFncomms12082_CR7","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.neuron.2010.10.013","volume":"68","author":"L Bertram","year":"2010","unstructured":"Bertram, L., Lill, C. M. & Tanzi, R. E. The genetics of Alzheimer disease: back to the future. Neuron 68, 270\u2013281 (2010).","journal-title":"Neuron"},{"key":"BFncomms12082_CR8","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1126\/science.1566067","volume":"256","author":"JA Hardy","year":"1992","unstructured":"Hardy, J. A. & Higgins, G. A. Alzheimer\u2019s disease: the amyloid cascade hypothesis. Science 256, 184\u2013185 (1992).","journal-title":"Science"},{"key":"BFncomms12082_CR9","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1126\/science.1062097","volume":"293","author":"J Gotz","year":"2001","unstructured":"Gotz, J., Chen, F., Van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P3011 tau transgenic mice induced by Abeta fibrils. Science 293, 1491\u20131495 (2001).","journal-title":"Science"},{"key":"BFncomms12082_CR10","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1126\/science.1058189","volume":"293","author":"J Lewis","year":"2001","unstructured":"Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutat tau and APP. Science 293, 1487\u20131491 (2001).","journal-title":"Science"},{"key":"BFncomms12082_CR11","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.neuron.2004.07.003","volume":"43","author":"S Oddo","year":"2004","unstructured":"Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321\u2013332 (2004).","journal-title":"Neuron"},{"key":"BFncomms12082_CR12","doi-asserted-by":"publisher","first-page":"12163","DOI":"10.1523\/JNEUROSCI.2464-08.2008","volume":"28","author":"S Oddo","year":"2008","unstructured":"Oddo, S. et al. Blocking A\u03b242 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein 70-interacting protein: a mechanistic link between alpha beta and tau pathology. J. Neurosci. 28, 12163\u201312175 (2008).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR13","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/j.neurobiolaging.2007.04.014","volume":"29","author":"BP Tseng","year":"2008","unstructured":"Tseng, B. P., Green, K. N., Chan, J. L., Blurton-Jones, M. & LaFerla, F. M. A\u00df inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol. Aging 29, 1607\u20131618 (2008).","journal-title":"Neurobiol. Aging"},{"key":"BFncomms12082_CR14","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/349704a0","volume":"349","author":"A Goate","year":"1991","unstructured":"Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease. Nature 349, 704\u2013706 (1991).","journal-title":"Nature"},{"key":"BFncomms12082_CR15","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/375754a0","volume":"375","author":"R Sherrington","year":"1995","unstructured":"Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2019s disease. Nature 375, 754\u2013760 (1995).","journal-title":"Nature"},{"key":"BFncomms12082_CR16","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","volume":"90","author":"WJ Strittmatter","year":"1993","unstructured":"Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to b-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977\u20131981 (1993).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12082_CR17","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/S0896-6273(03)00850-X","volume":"41","author":"RB DeMattos","year":"2004","unstructured":"DeMattos, R. B. et al. ApoE and clusterin cooperatively suppress A\u03b2 levels and deposition. Evidence that ApoE regulates extracellular A\u03b2 metabolism in vivo. Neuron 41, 193\u2013202 (2004).","journal-title":"Neuron"},{"key":"BFncomms12082_CR18","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nrn2620","volume":"10","author":"G Bu","year":"2009","unstructured":"Bu, G. Apolipoprotein E and its receptors in Alzheimer\u2019s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333\u2013344 (2009).","journal-title":"Nat. Rev. Neurosci."},{"key":"BFncomms12082_CR19","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.neuron.2009.06.026","volume":"63","author":"J Kim","year":"2009","unstructured":"Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer\u2019s disease. Neuron 63, 287\u2013303 (2009).","journal-title":"Neuron"},{"key":"BFncomms12082_CR20","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","volume":"368","author":"R Guerreiro","year":"2013","unstructured":"Guerreiro, R. et al. TREM2 variants in Alzheimer\u2019s disease. N. Engl. J. Med. 368, 117\u2013127 (2013).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12082_CR21","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1056\/NEJMoa1211103","volume":"368","author":"T Jonsson","year":"2013","unstructured":"Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer\u2019s disease. N. Engl. J. Med. 368, 107\u2013116 (2013).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12082_CR22","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.1212\/WNL.38.11.1682","volume":"38","author":"HA Crystal","year":"1988","unstructured":"Crystal, H. A. et al. Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer\u2019s disease. Neurology 38, 1682\u20131687 (1988).","journal-title":"Neurology"},{"key":"BFncomms12082_CR23","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1002\/ana.410230206","volume":"23","author":"R Katzman","year":"1988","unstructured":"Katzman, R. et al. Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann. Neurol. 23, 138\u2013144 (1988).","journal-title":"Ann. Neurol."},{"key":"BFncomms12082_CR24","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/1531-8249(199903)45:3<358::AID-ANA12>3.0.CO;2-X","volume":"45","author":"JL Price","year":"1999","unstructured":"Price, J. L. & Morris, J. C. Tangles and plaques in nondemented aging and \u2018preclinical\u2019 Alzheimer\u2019s disease. Ann. Neurol. 45, 358\u2013368 (1999).","journal-title":"Ann. Neurol."},{"key":"BFncomms12082_CR25","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1212\/WNL.42.3.631","volume":"42","author":"PV Arriagada","year":"1992","unstructured":"Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer\u2019s disease. Neurology 42, 631\u2013639 (1992).","journal-title":"Neurology"},{"key":"BFncomms12082_CR26","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1212\/WNL.42.9.1681","volume":"42","author":"PV Arriagada","year":"1992","unstructured":"Arriagada, P. V., Marzloff, K. & Hyman, B. T. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer\u2019s disease. Neurology 42, 1681\u20131688 (1992).","journal-title":"Neurology"},{"key":"BFncomms12082_CR27","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/ana.410410106","volume":"41","author":"T Gomez-Isla","year":"1997","unstructured":"Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer\u2019s disease. Ann. Neurol. 41, 17\u201324 (1997).","journal-title":"Ann. Neurol."},{"key":"BFncomms12082_CR28","doi-asserted-by":"crossref","unstructured":"Price, D., Savonenko, A. V., Li, T., Lee, M. K. & Wong, P. in Alzheimer Disease: Protein Misfolding, Model Systems, and Experimental Therapeutics in Protein Misfolding Diseases eds Ramirez-Alvarado M., Kelly J. W., Dobson C. M. 233\u2013258John Wiley & Sons, Inc. (2010).","DOI":"10.1002\/9780470572702.ch12"},{"key":"BFncomms12082_CR29","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1038\/nrn2420","volume":"9","author":"J Gotz","year":"2008","unstructured":"Gotz, J. & Ittner, L. M. Animal models of Alzheimer\u2019s disease and frontotemporal dementia. Nat. Rev. Neurosci. 9, 532\u2013544 (2008).","journal-title":"Nat. Rev. Neurosci."},{"key":"BFncomms12082_CR30","doi-asserted-by":"publisher","first-page":"a006320","DOI":"10.1101\/cshperspect.a006320","volume":"2","author":"FM LaFerla","year":"2012","unstructured":"LaFerla, F. M. & Green, K. N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006320 (2012).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"BFncomms12082_CR31","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1517\/17460441.2012.666234","volume":"7","author":"KR Bales","year":"2012","unstructured":"Bales, K. R. The value and limitations of transgenic mouse models used in drug discovery for Alzheimer\u2019s disease: an update. Expert. Opin. Drug Discov. 7, 281\u2013297 (2012).","journal-title":"Expert. Opin. Drug Discov."},{"key":"BFncomms12082_CR32","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.bbadis.2013.04.017","volume":"1832","author":"TL Platt","year":"2013","unstructured":"Platt, T. L., Reeves, V. L. & Murphy, M. P. Transgenic models of Alzheimer\u2019s disease: better utilization of existing models through viral transgenesis. Biochim. Biophys. Acta 1832, 1437\u20131448 (2013).","journal-title":"Biochim. Biophys. Acta"},{"key":"BFncomms12082_CR33","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.2174\/138161212799315786","volume":"18","author":"M Kitazawa","year":"2012","unstructured":"Kitazawa, M., Medeiros, R. & LaFerla, F. M. Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr. Pharm. Des. 18, 1131\u20131147 (2012).","journal-title":"Curr. Pharm. Des."},{"key":"BFncomms12082_CR34","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0896-6273(03)00434-3","volume":"39","author":"S Oddo","year":"2003","unstructured":"Oddo, S. et al. Triple-transgenic model of Alzheimer\u2019s disease with plaques and tangles: intracellular A\u03b2 and synaptic dysfunction. Neuron 39, 409\u2013421 (2003).","journal-title":"Neuron"},{"key":"BFncomms12082_CR35","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/78078","volume":"25","author":"J Lewis","year":"2000","unstructured":"Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402\u2013405 (2000).","journal-title":"Nat. Genet."},{"key":"BFncomms12082_CR36","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.neuron.2007.03.022","volume":"54","author":"Y Yoshiyama","year":"2007","unstructured":"Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse mode (vol 53, pg 337, 2007). Neuron 54, 343\u2013344 (2007).","journal-title":"Neuron"},{"key":"BFncomms12082_CR37","doi-asserted-by":"publisher","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":"BFncomms12082_CR38","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1126\/science.274.5284.99","volume":"274","author":"K Hsiao","year":"1996","unstructured":"Hsiao, K. et al. Correlative memory deficts, A\u03b2 elevation and amyloid plaques in transgenic mice. Science 274, 99\u2013102 (1996).","journal-title":"Science"},{"key":"BFncomms12082_CR39","doi-asserted-by":"publisher","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","volume":"26","author":"H Oakley","year":"2006","unstructured":"Oakley, H. et al. Intraneuronal \u03b2-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129\u201310140 (2006).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR40","doi-asserted-by":"publisher","first-page":"13287","DOI":"10.1073\/pnas.94.24.13287","volume":"94","author":"C Sturchler-Pierrat","year":"1997","unstructured":"Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287\u201313292 (1997).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12082_CR41","doi-asserted-by":"publisher","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":"BFncomms12082_CR42","doi-asserted-by":"publisher","first-page":"7691","DOI":"10.1523\/JNEUROSCI.6637-10.2011","volume":"31","author":"MJ Winton","year":"2011","unstructured":"Winton, M. J. et al. Intraneuronal APP, not free A\u03b2 peptides in 3xTg-AD mice: implications for tau versus A\u03b2-mediated Alzheimer neurodegeneration. J. Neurosci. 31, 7691\u20137699 (2011).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR43","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/j.neuron.2014.04.047","volume":"82","author":"DW Sanders","year":"2014","unstructured":"Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271\u20131288 (2014).","journal-title":"Neuron"},{"key":"BFncomms12082_CR44","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/31508","volume":"393","author":"M Hutton","year":"1998","unstructured":"Hutton, M. et al. Association of missense and 5\u2019-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702\u2013705 (1998).","journal-title":"Nature"},{"key":"BFncomms12082_CR45","doi-asserted-by":"publisher","first-page":"10252","DOI":"10.1073\/pnas.0703676104","volume":"104","author":"YP Wang","year":"2007","unstructured":"Wang, Y. P., Biernat, J., Pickhardt, M., Mandelkow, E. & Mandelkow, E. M. Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc. Natl Acad. Sci. USA 104, 10252\u201310257 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms12082_CR46","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1093\/brain\/aws013","volume":"135","author":"DJ Irwin","year":"2012","unstructured":"Irwin, D. J. et al. Acetylated tau, a novel pathological signature in Alzheimer\u2019s disease and other tauopathies. Brain 135, 807\u2013818 (2012).","journal-title":"Brain"},{"key":"BFncomms12082_CR47","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/ncomms1255","volume":"2","author":"TJ Cohen","year":"2011","unstructured":"Cohen, T. J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2, 252 (2011).","journal-title":"Nat. Commun."},{"key":"BFncomms12082_CR48","doi-asserted-by":"publisher","first-page":"e355","DOI":"10.1371\/journal.pmed.0020355","volume":"2","author":"JL Jankowsky","year":"2005","unstructured":"Jankowsky, J. L. et al. Persistent amyloidosis following suppression of A\u03b2 production in a transgenic model of Alzheimer disease. PLoS. Med. 2, e355 (2005).","journal-title":"PLoS. Med."},{"key":"BFncomms12082_CR49","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1093\/jnen\/62.12.1220","volume":"62","author":"JL Jankowsky","year":"2003","unstructured":"Jankowsky, J. L., Xu, G., Fromholt, D., Gonzales, V. & Borchelt, D. R. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol. Exp. Neurol 62, 1220\u20131227 (2003).","journal-title":"J Neuropathol. Exp. Neurol"},{"key":"BFncomms12082_CR50","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1523\/JNEUROSCI.2824-07.2008","volume":"28","author":"MM Mocanu","year":"2008","unstructured":"Mocanu, M. M. et al. The potential for beta-structure in the repeat domain of Tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 28, 737\u2013748 (2008).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR51","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1038\/ng.440","volume":"41","author":"D Harold","year":"2009","unstructured":"Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer\u2019s disease. Nat. Genet. 41, 1088\u20131093 (2009).","journal-title":"Nat. Genet."},{"key":"BFncomms12082_CR52","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1038\/ng.439","volume":"41","author":"JC Lambert","year":"2009","unstructured":"Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer\u2019s disease. Nat. Genet. 41, 1094\u20131099 (2009).","journal-title":"Nat. Genet."},{"key":"BFncomms12082_CR53","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/ng.803","volume":"43","author":"P Hollingworth","year":"2011","unstructured":"Hollingworth, P. et al. Common variants at ABCA7, MS4A6A\/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer\u2019s disease. Nat. Genet. 43, 429\u2013435 (2011).","journal-title":"Nat. Genet."},{"key":"BFncomms12082_CR54","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1038\/ng.801","volume":"43","author":"AC Naj","year":"2011","unstructured":"Naj, A. C. et al. Common variants at MS4A4\/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset alzheimer\u2019s disease. Nat. Genet. 43, 436\u2013441 (2011).","journal-title":"Nat. Genet."},{"key":"BFncomms12082_CR55","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.neuron.2013.12.003","volume":"80","author":"CR Jack Jr","year":"2013","unstructured":"Jack, C. R. Jr & Holtzman, D. M. Biomarker modeling of Alzheimer\u2019s disease. Neuron 80, 1347\u20131358 (2013).","journal-title":"Neuron"},{"key":"BFncomms12082_CR56","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S1474-4422(12)70291-0","volume":"12","author":"CR Jack Jr","year":"2013","unstructured":"Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer\u2019s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207\u2013216 (2013).","journal-title":"Lancet Neurol."},{"key":"BFncomms12082_CR57","unstructured":"Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer\u2019s disease. Nature (2014)."},{"key":"BFncomms12082_CR58","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.neuron.2011.01.002","volume":"69","author":"TE Golde","year":"2011","unstructured":"Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-A\u03b2 therapeutics in Alzheimer\u2019s disease: the need for a paradigm shift. Neuron 69, 203\u2013213 (2011).","journal-title":"Neuron"},{"key":"BFncomms12082_CR59","doi-asserted-by":"crossref","unstructured":"Sperling, R. A., Jack, C. R. Jr & Aisen, P. S. Testing the right target and right drug at the right stage. Sci. Transl. Med. 30, 111cm33 (2011).","DOI":"10.1126\/scitranslmed.3002609"},{"key":"BFncomms12082_CR60","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1056\/NEJMoa1304839","volume":"370","author":"S Salloway","year":"2014","unstructured":"Salloway, S., Sperling, R. & Brashear, H. R. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer\u2019s disease. N. Engl. J. Med. 370, 1460 (2014).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12082_CR61","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1056\/NEJMoa1312889","volume":"370","author":"RS Doody","year":"2014","unstructured":"Doody, R. S., Farlow, M. & Aisen, P. S. Phase 3 trials of solanezumab and bapineuzumab for Alzheimer\u2019s disease. N. Engl. J. Med. 370, 1460 (2014).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms12082_CR62","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1126\/science.274.5293.1678","volume":"274","author":"M Mayford","year":"1996","unstructured":"Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678\u20131683 (1996).","journal-title":"Science"},{"key":"BFncomms12082_CR63","doi-asserted-by":"publisher","first-page":"3272","DOI":"10.1523\/JNEUROSCI.23-08-03272.2003","volume":"23","author":"T Li","year":"2003","unstructured":"Li, T., Ma, G., Cai, H., Price, D. L. & Wong, P. C. Nicastrin is required for assembly of presenilin\/gamma -secretase complexes to mediate notch signaling and for processing and trafficking of \u03b2 -amyloid precursor protein in mammals. J. Neurosci. 23, 3272\u20133277 (2003).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR64","doi-asserted-by":"publisher","first-page":"10849","DOI":"10.1523\/JNEUROSCI.2152-07.2007","volume":"27","author":"T Li","year":"2007","unstructured":"Li, T. et al. Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities. J. Neurosci. 27, 10849\u201310859 (2007).","journal-title":"J. Neurosci."},{"key":"BFncomms12082_CR65","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/j.1365-2990.1986.tb00677.x","volume":"12","author":"T Yamamoto","year":"1986","unstructured":"Yamamoto, T. & Hirano, A. A comparative study of modified Bielschowsky, Bodian and thioflavin S stains on Alzheimer\u2019s neurofibrillary tangles. Neuropathol. Appl. Neurobiol. 12, 3\u20139 (1986).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"BFncomms12082_CR66","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/S0896-6273(00)80230-5","volume":"17","author":"DR Borchelt","year":"1996","unstructured":"Borchelt, D. R. et al. Familial Alzheimer\u2019s disease-linked presenilin 1 variants elevate A\u03b21-42\/1-40 ratio in vitro and in vivo. Neuron 17, 1005\u20131013 (1996).","journal-title":"Neuron"},{"key":"BFncomms12082_CR67","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","volume":"82","author":"H Braak","year":"1991","unstructured":"Braak, H. & Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, 239\u2013259 (1991).","journal-title":"Acta Neuropathol."},{"key":"BFncomms12082_CR68","first-page":"132","volume":"117","author":"SS Mirra","year":"1993","unstructured":"Mirra, S. S., Hart, M. H. & Terry, R. D. Making the diagnosis of Alzheimer\u2019s disease. A primer for practicing pathologists. Arch. Pathol. Lab. Med. 117, 132\u2013144 (1993).","journal-title":"Arch. Pathol. Lab. Med."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms12082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12082","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms12082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T11:14:16Z","timestamp":1672830856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms12082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,4]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,25]]}},"alternative-id":["BFncomms12082"],"URL":"https:\/\/doi.org\/10.1038\/ncomms12082","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,4]]},"assertion":[{"value":"11 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2016","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":"12082"}}