{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:03:57Z","timestamp":1788458637805,"version":"build-2803163510"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007457","name":"JPB Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100007457","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1R01NS119280"],"award-info":[{"award-number":["1R01NS119280"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Neurosci"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of\n                    <jats:italic>Tyk2<\/jats:italic>\n                    reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.\n                  <\/jats:p>","DOI":"10.1038\/s41593-024-01777-2","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T05:02:45Z","timestamp":1731301365000},"page":"2417-2429","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model"],"prefix":"10.1038","volume":"27","author":[{"given":"Jiyoen","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakhos","family":"Tadros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Hong","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-7371","authenticated-orcid":false,"given":"Youngdoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5499-3082","authenticated-orcid":false,"given":"Cristian","family":"Lasagna-Reeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Young","family":"Sonn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dah-eun Chloe","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-9401","authenticated-orcid":false,"given":"Bradley","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-0856","authenticated-orcid":false,"given":"David M.","family":"Holtzman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0700-3349","authenticated-orcid":false,"given":"Huda Yahya","family":"Zoghbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"1777_CR1","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1111\/j.1445-5994.2006.01153.x","volume":"36","author":"DR Williams","year":"2006","unstructured":"Williams, D. R. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern. Med. J. 36, 652\u2013660 (2006).","journal-title":"Intern. Med. J."},{"key":"1777_CR2","doi-asserted-by":"publisher","first-page":"595532","DOI":"10.3389\/fneur.2020.595532","volume":"11","author":"C Alquezar","year":"2020","unstructured":"Alquezar, C., Arya, S. & Kao, A. W. Tau post-translational modifications: dynamic transformers of tau function, degradation, and aggregation. Front. Neurol. 11, 595532 (2020).","journal-title":"Front. Neurol."},{"key":"1777_CR3","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1016\/j.cell.2020.10.029","volume":"183","author":"H Wesseling","year":"2020","unstructured":"Wesseling, H. et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer\u2019s disease. Cell 183, 1699\u20131713 (2020).","journal-title":"Cell"},{"key":"1777_CR4","doi-asserted-by":"publisher","first-page":"581936","DOI":"10.3389\/fnins.2020.581936","volume":"14","author":"F Kametani","year":"2020","unstructured":"Kametani, F. et al. Comparison of common and disease-specific post-translational modifications of pathological tau associated with a wide range of tauopathies. Front. Neurosci. 14, 581936 (2020).","journal-title":"Front. Neurosci."},{"key":"1777_CR5","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s40478-019-0823-2","volume":"7","author":"E Ercan-Herbst","year":"2019","unstructured":"Ercan-Herbst, E. et al. A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer\u2019s disease brain. Acta Neuropathol. Commun. 7, 192 (2019).","journal-title":"Acta Neuropathol. Commun."},{"key":"1777_CR6","doi-asserted-by":"publisher","first-page":"944806","DOI":"10.3389\/fneur.2022.944806","volume":"13","author":"N Olfati","year":"2022","unstructured":"Olfati, N., Shoeibi, A. & Litvan, I. Clinical spectrum of tauopathies. Front. Neurol. 13, 944806 (2022).","journal-title":"Front. Neurol."},{"key":"1777_CR7","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1002\/alz.12452","volume":"18","author":"C Sexton","year":"2022","unstructured":"Sexton, C. et al. Current directions in tau research: highlights from Tau 2020. Alzheimers Dement. 18, 988\u20131007 (2022).","journal-title":"Alzheimers Dement."},{"key":"1777_CR8","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1042\/BST20120045","volume":"40","author":"A Rovelet-Lecrux","year":"2012","unstructured":"Rovelet-Lecrux, A. & Campion, D. Copy number variations involving the microtubule-associated protein tau in human diseases. Biochem. Soc. Trans. 40, 672\u2013676 (2012).","journal-title":"Biochem. Soc. Trans."},{"key":"1777_CR9","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.2353\/ajpath.2009.090462","volume":"175","author":"SJ Adams","year":"2009","unstructured":"Adams, S. J. et al. Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration. Am. J. Pathol. 175, 1598\u20131609 (2009).","journal-title":"Am. J. Pathol."},{"key":"1777_CR10","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1126\/science.1141736","volume":"316","author":"ED Roberson","year":"2007","unstructured":"Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid \u03b2-induced deficits in an Alzheimer\u2019s disease mouse model. Science 316, 750\u2013754 (2007).","journal-title":"Science"},{"key":"1777_CR11","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.neuron.2016.09.022","volume":"92","author":"CA Lasagna-Reeves","year":"2016","unstructured":"Lasagna-Reeves, C. A. et al. Reduction of Nuak1 decreases tau and reverses phenotypes in a tauopathy mouse model. Neuron 92, 407\u2013418 (2016).","journal-title":"Neuron"},{"key":"1777_CR12","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.neuron.2022.12.012","volume":"111","author":"J Kim","year":"2023","unstructured":"Kim, J. et al. Evolutionarily conserved regulators of tau identify targets for new therapies. Neuron 111, 824\u2013838 (2023).","journal-title":"Neuron"},{"key":"1777_CR13","doi-asserted-by":"publisher","first-page":"20775","DOI":"10.1074\/jbc.270.35.20775","volume":"270","author":"FW Quelle","year":"1995","unstructured":"Quelle, F. W. et al. Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor. J. Biol. Chem. 270, 20775\u201320780 (1995).","journal-title":"J. Biol. Chem."},{"key":"1777_CR14","doi-asserted-by":"publisher","first-page":"32507","DOI":"10.1074\/jbc.274.45.32507","volume":"274","author":"MR Rani","year":"1999","unstructured":"Rani, M. R. et al. Catalytically active TYK2 is essential for interferon-\u03b2-mediated phosphorylation of STAT3 and interferon-\u03b1 receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase. J. Biol. Chem. 274, 32507\u201332511 (1999).","journal-title":"J. Biol. Chem."},{"key":"1777_CR15","first-page":"8133","volume":"14","author":"O Colamonici","year":"1994","unstructured":"Colamonici, O. et al. Direct binding to and tyrosine phosphorylation of the \u03b1 subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol. Cell. Biol. 14, 8133\u20138142 (1994).","journal-title":"Mol. Cell. Biol."},{"key":"1777_CR16","doi-asserted-by":"publisher","unstructured":"K\u00f6nig, L. E. et al. TYK2 as a novel therapeutic target in Alzheimer\u2019s disease with TDP-43 inclusions. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2024.06.04.595773 (2023).","DOI":"10.1101\/2024.06.04.595773"},{"key":"1777_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JAD-2009-1116","volume":"18","author":"T Lebouvier","year":"2009","unstructured":"Lebouvier, T. et al. The microtubule-associated protein tau is also phosphorylated on tyrosine. J. Alzheimers Dis. 18, 1\u20139 (2009).","journal-title":"J. Alzheimers Dis."},{"key":"1777_CR18","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1111\/j.1365-2990.2010.01103.x","volume":"36","author":"K Bhaskar","year":"2010","unstructured":"Bhaskar, K., Hobbs, G. A., Yen, S. H. & Lee, G. Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy. Neuropathol. Appl. Neurobiol. 36, 462\u2013477 (2010).","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"1777_CR19","doi-asserted-by":"publisher","first-page":"108045","DOI":"10.1016\/j.celrep.2020.108045","volume":"32","author":"A Briner","year":"2020","unstructured":"Briner, A., Gotz, J. & Polanco, J. C. Fyn kinase controls tau aggregation in vivo. Cell Rep. 32, 108045 (2020).","journal-title":"Cell Rep."},{"key":"1777_CR20","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.molbrainres.2005.04.015","volume":"138","author":"IE Vega","year":"2005","unstructured":"Vega, I. E. et al. Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res. Mol. Brain Res. 138, 135\u2013144 (2005).","journal-title":"Brain Res. Mol. Brain Res."},{"key":"1777_CR21","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3233\/JAD-180054","volume":"64","author":"C Li","year":"2018","unstructured":"Li, C. & Gotz, J. Pyk2 is a novel tau tyrosine kinase that is regulated by the tyrosine kinase Fyn. J. Alzheimers Dis. 64, 205\u2013221 (2018).","journal-title":"J. Alzheimers Dis."},{"key":"1777_CR22","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1750-1326-6-12","volume":"6","author":"TM Scales","year":"2011","unstructured":"Scales, T. M. et al. Tyrosine phosphorylation of tau by the SRC family kinases Lck and Fyn. Mol. Neurodegener. 6, 12 (2011).","journal-title":"Mol. Neurodegener."},{"key":"1777_CR23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s40478-016-0317-4","volume":"4","author":"DH Lau","year":"2016","unstructured":"Lau, D. H. et al. Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer\u2019s disease. Acta Neuropathol. Commun. 4, 49 (2016).","journal-title":"Acta Neuropathol. Commun."},{"key":"1777_CR24","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.bbamcr.2007.11.005","volume":"1783","author":"T Lebouvier","year":"2008","unstructured":"Lebouvier, T. et al. The microtubule-associated protein tau is phosphorylated by Syk. Biochim. Biophys. Acta 1783, 188\u2013192 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"1777_CR25","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1111\/j.1471-4159.2006.04059.x","volume":"98","author":"S Sato","year":"2006","unstructured":"Sato, S., Cerny, R. L., Buescher, J. L. & Ikezu, T. Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J. Neurochem. 98, 1573\u20131584 (2006).","journal-title":"J. Neurochem."},{"key":"1777_CR26","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1111\/bpa.12001","volume":"23","author":"H Lund","year":"2013","unstructured":"Lund, H. et al. Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer\u2019s disease brain. Brain Pathol. 23, 378\u2013389 (2013).","journal-title":"Brain Pathol."},{"key":"1777_CR27","doi-asserted-by":"publisher","first-page":"6584","DOI":"10.1523\/JNEUROSCI.1487-05.2005","volume":"25","author":"P Derkinderen","year":"2005","unstructured":"Derkinderen, P. et al. Tyrosine 394 is phosphorylated in Alzheimer\u2019s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J. Neurosci. 25, 6584\u20136593 (2005).","journal-title":"J. Neurosci."},{"key":"1777_CR28","doi-asserted-by":"publisher","first-page":"721","DOI":"10.3233\/JAD-2010-1271","volume":"19","author":"MA Tremblay","year":"2010","unstructured":"Tremblay, M. A., Acker, C. M. & Davies, P. Tau phosphorylated at tyrosine 394 is found in Alzheimer\u2019s disease tangles and can be a product of the Abl-related kinase, Arg. J. Alzheimers Dis. 19, 721\u2013733 (2010).","journal-title":"J. Alzheimers Dis."},{"key":"1777_CR29","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1021\/bi047982v","volume":"44","author":"MR Reynolds","year":"2005","unstructured":"Reynolds, M. R., Berry, R. W. & Binder, L. I. Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer\u2019s disease. Biochemistry 44, 1690\u20131700 (2005).","journal-title":"Biochemistry"},{"key":"1777_CR30","doi-asserted-by":"publisher","first-page":"13997","DOI":"10.1021\/bi051028w","volume":"44","author":"MR Reynolds","year":"2005","unstructured":"Reynolds, M. R., Berry, R. W. & Binder, L. I. Site-specific nitration differentially influences tau assembly in vitro. Biochemistry 44, 13997\u201314009 (2005).","journal-title":"Biochemistry"},{"key":"1777_CR31","doi-asserted-by":"publisher","first-page":"10636","DOI":"10.1523\/JNEUROSCI.2143-06.2006","volume":"26","author":"MR Reynolds","year":"2006","unstructured":"Reynolds, M. R. et al. Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer\u2019s disease and other tauopathies. J. Neurosci. 26, 10636\u201310645 (2006).","journal-title":"J. Neurosci."},{"key":"1777_CR32","doi-asserted-by":"publisher","first-page":"11594","DOI":"10.1073\/pnas.1930781100","volume":"100","author":"MH Shaw","year":"2003","unstructured":"Shaw, M. H. et al. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q\/J mice to infection and autoimmunity. Proc. Natl Acad. Sci. USA 100, 11594\u201311599 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1777_CR33","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.neuron.2013.07.046","volume":"80","author":"K Yanamandra","year":"2013","unstructured":"Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402\u2013414 (2013).","journal-title":"Neuron"},{"key":"1777_CR34","doi-asserted-by":"publisher","first-page":"jcs229054","DOI":"10.1242\/jcs.229054","volume":"132","author":"Y Kim","year":"2019","unstructured":"Kim, Y. et al. Tau interacts with SHP2 in neuronal systems and in Alzheimer\u2019s disease brains. J. Cell Sci. 132, jcs229054 (2019).","journal-title":"J. Cell Sci."},{"key":"1777_CR35","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1046\/j.1471-4159.1995.65020732.x","volume":"65","author":"CX Gong","year":"1995","unstructured":"Gong, C. X. et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J. Neurochem. 65, 732\u2013738 (1995).","journal-title":"J. Neurochem."},{"key":"1777_CR36","doi-asserted-by":"publisher","first-page":"8025","DOI":"10.1073\/pnas.1401180111","volume":"111","author":"PJ Lupardus","year":"2014","unstructured":"Lupardus, P. J. et al. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl Acad. Sci. USA 111, 8025\u20138030 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1777_CR37","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1093\/hmg\/ddm320","volume":"17","author":"JM Tan","year":"2008","unstructured":"Tan, J. M. et al. Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. Hum. Mol. Genet. 17, 431\u2013439 (2008).","journal-title":"Hum. Mol. Genet."},{"key":"1777_CR38","doi-asserted-by":"publisher","first-page":"85","DOI":"10.4161\/auto.5172","volume":"4","author":"JA Olzmann","year":"2008","unstructured":"Olzmann, J. A. & Chin, L. S. Parkin-mediated K63-linked polyubiquitination: a signal for targeting misfolded proteins to the aggresome-autophagy pathway. Autophagy 4, 85\u201387 (2008).","journal-title":"Autophagy"},{"key":"1777_CR39","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/cr.2016.39","volume":"26","author":"KN Swatek","year":"2016","unstructured":"Swatek, K. N. & Komander, D. Ubiquitin modifications. Cell Res. 26, 399\u2013422 (2016).","journal-title":"Cell Res."},{"key":"1777_CR40","doi-asserted-by":"publisher","first-page":"E4762","DOI":"10.1073\/pnas.1319948110","volume":"110","author":"JM Drake","year":"2013","unstructured":"Drake, J. M. et al. Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets. Proc. Natl Acad. Sci. USA 110, E4762\u2013E4769 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1777_CR41","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1007\/s00401-016-1663-9","volume":"133","author":"P Wang","year":"2017","unstructured":"Wang, P. et al. Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo. Acta Neuropathol. 133, 731\u2013749 (2017).","journal-title":"Acta Neuropathol."},{"key":"1777_CR42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10278-x","volume":"10","author":"S Hashimoto","year":"2019","unstructured":"Hashimoto, S. et al. Tau binding protein CAPON induces tau aggregation and neurodegeneration. Nat. Commun. 10, 2394 (2019).","journal-title":"Nat. Commun."},{"key":"1777_CR43","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1111\/ejn.12126","volume":"37","author":"JY Kim","year":"2013","unstructured":"Kim, J. Y. et al. Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo. Eur. J. Neurosci. 37, 1203\u20131220 (2013).","journal-title":"Eur. J. Neurosci."},{"key":"1777_CR44","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.neuron.2007.01.010","volume":"53","author":"Y Yoshiyama","year":"2007","unstructured":"Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337\u2013351 (2007).","journal-title":"Neuron"},{"key":"1777_CR45","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/0304-3940(92)90774-2","volume":"147","author":"DP Hanger","year":"1992","unstructured":"Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P. & Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimer\u2019s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58\u201362 (1992).","journal-title":"Neurosci. Lett."},{"key":"1777_CR46","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0014-5793(93)81066-9","volume":"325","author":"K Ishiguro","year":"1993","unstructured":"Ishiguro, K. et al. Glycogen synthase kinase 3 \u03b2 is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 325, 167\u2013172 (1993).","journal-title":"FEBS Lett."},{"key":"1777_CR47","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/0304-3940(95)12206-0","volume":"202","author":"K Ishiguro","year":"1995","unstructured":"Ishiguro, K. et al. Analysis of phosphorylation of tau with antibodies specific for phosphorylation sites. Neurosci. Lett. 202, 81\u201384 (1995).","journal-title":"Neurosci. Lett."},{"key":"1777_CR48","doi-asserted-by":"publisher","first-page":"E4376","DOI":"10.1073\/pnas.1411649111","volume":"111","author":"BB Holmes","year":"2014","unstructured":"Holmes, B. B. et al. Proteopathic tau seeding predicts tauopathy in vivo. Proc. Natl Acad. Sci. USA 111, E4376\u2013E4385 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1777_CR49","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s40478-017-0442-8","volume":"5","author":"SK Kaufman","year":"2017","unstructured":"Kaufman, S. K., Thomas, T. L., Del Tredici, K., Braak, H. & Diamond, M. I. Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue. Acta Neuropathol. Commun. 5, 41 (2017).","journal-title":"Acta Neuropathol. Commun."},{"key":"1777_CR50","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.arr.2012.06.003","volume":"12","author":"L Martin","year":"2013","unstructured":"Martin, L. et al. Tau protein kinases: involvement in Alzheimer\u2019s disease. Ageing Res. Rev. 12, 289\u2013309 (2013).","journal-title":"Ageing Res. Rev."},{"key":"1777_CR51","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.neurobiolaging.2009.07.007","volume":"32","author":"GI Cancino","year":"2011","unstructured":"Cancino, G. I. et al. c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice. Neurobiol. Aging 32, 1249\u20131261 (2011).","journal-title":"Neurobiol. Aging"},{"key":"1777_CR52","doi-asserted-by":"publisher","first-page":"7905","DOI":"10.1074\/jbc.RA119.012517","volume":"295","author":"N Ait-Bouziad","year":"2020","unstructured":"Ait-Bouziad, N. et al. Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau. J. Biol. Chem. 295, 7905\u20137922 (2020).","journal-title":"J. Biol. Chem."},{"key":"1777_CR53","doi-asserted-by":"publisher","first-page":"6873","DOI":"10.1523\/JNEUROSCI.0519-10.2010","volume":"30","author":"J Wan","year":"2010","unstructured":"Wan, J. et al. Tyk2\/STAT3 signaling mediates \u03b2-amyloid-induced neuronal cell death: implications in Alzheimer\u2019s disease. J. Neurosci. 30, 6873\u20136881 (2010).","journal-title":"J. Neurosci."},{"key":"1777_CR54","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1042\/BJ20101485","volume":"434","author":"C Thornton","year":"2011","unstructured":"Thornton, C., Bright, N. J., Sastre, M., Muckett, P. J. & Carling, D. AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid \u03b2-peptide exposure. Biochem. J. 434, 503\u2013512 (2011).","journal-title":"Biochem. J."},{"key":"1777_CR55","doi-asserted-by":"publisher","first-page":"12230","DOI":"10.1523\/JNEUROSCI.1694-14.2014","volume":"34","author":"T Ma","year":"2014","unstructured":"Ma, T. et al. Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid \u03b2. J. Neurosci. 34, 12230\u201312238 (2014).","journal-title":"J. Neurosci."},{"key":"1777_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/srep26758","volume":"6","author":"M Domise","year":"2016","unstructured":"Domise, M. et al. AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci. Rep. 6, 26758 (2016).","journal-title":"Sci. Rep."},{"key":"1777_CR57","doi-asserted-by":"publisher","first-page":"eaay6931","DOI":"10.1126\/scitranslmed.aay6931","volume":"12","author":"F Zhang","year":"2020","unstructured":"Zhang, F. et al. \u03b2-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3\u03b2\/tau cascade. Sci. Transl. Med. 12, eaay6931 (2020).","journal-title":"Sci. Transl. Med."},{"key":"1777_CR58","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1038\/s41593-020-0687-6","volume":"23","author":"MA Busche","year":"2020","unstructured":"Busche, M. A. & Hyman, B. T. Synergy between amyloid-\u03b2 and tau in Alzheimer\u2019s disease. Nat. Neurosci. 23, 1183\u20131193 (2020).","journal-title":"Nat. Neurosci."},{"key":"1777_CR59","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13024-019-0340-6","volume":"14","author":"G Gallardo","year":"2019","unstructured":"Gallardo, G. et al. Targeting tauopathy with engineered tau-degrading intrabodies. Mol. Neurodegener. 14, 38 (2019).","journal-title":"Mol. Neurodegener."},{"key":"1777_CR60","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1002\/acn3.176","volume":"2","author":"K Yanamandra","year":"2015","unstructured":"Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl. Neurol. 2, 278\u2013288 (2015).","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"1777_CR61","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S1074-7613(00)00054-6","volume":"13","author":"M Karaghiosoff","year":"2000","unstructured":"Karaghiosoff, M. et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 13, 549\u2013560 (2000).","journal-title":"Immunity"},{"key":"1777_CR62","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.immuni.2006.09.009","volume":"25","author":"Y Minegishi","year":"2006","unstructured":"Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745\u2013755 (2006).","journal-title":"Immunity"},{"key":"1777_CR63","doi-asserted-by":"publisher","first-page":"4314","DOI":"10.1021\/bi052142h","volume":"45","author":"MR Reynolds","year":"2006","unstructured":"Reynolds, M. R., Lukas, T. J., Berry, R. W. & Binder, L. I. Peroxynitrite-mediated tau modifications stabilize preformed filaments and destabilize microtubules through distinct mechanisms. Biochemistry 45, 4314\u20134326 (2006).","journal-title":"Biochemistry"},{"key":"1777_CR64","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nbt.3807","volume":"35","author":"R Pelossof","year":"2017","unstructured":"Pelossof, R. et al. Prediction of potent shRNAs with a sequential classification algorithm. Nat. Biotechnol. 35, 350\u2013353 (2017).","journal-title":"Nat. Biotechnol."},{"key":"1777_CR65","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1016\/j.celrep.2013.11.020","volume":"5","author":"C Fellmann","year":"2013","unstructured":"Fellmann, C. et al. An optimized microRNA backbone for effective single-copy RNAi. Cell Rep. 5, 1704\u20131713 (2013).","journal-title":"Cell Rep."},{"key":"1777_CR66","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-15-28","volume":"15","author":"R Holehonnur","year":"2014","unstructured":"Holehonnur, R. et al. Adeno-associated viral serotypes produce differing titers and differentially transduce neurons within the rat basal and lateral amygdala. BMC Neurosci. 15, 28 (2014).","journal-title":"BMC Neurosci."},{"key":"1777_CR67","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/978-1-0716-0175-4_7","volume":"2092","author":"S Deng","year":"2020","unstructured":"Deng, S. & Oka, K. Adeno-associated virus as gene delivery vehicle into the retina. Methods Mol. Biol. 2092, 77\u201390 (2020).","journal-title":"Methods Mol. Biol."},{"key":"1777_CR68","doi-asserted-by":"publisher","first-page":"9286","DOI":"10.1523\/JNEUROSCI.0254-18.2018","volume":"38","author":"MWC Rousseaux","year":"2018","unstructured":"Rousseaux, M. W. C. et al. A druggable genome screen identifies modifiers of \u03b1-synuclein levels via a tiered cross-species validation approach. J. Neurosci. 38, 9286\u20139301 (2018).","journal-title":"J. Neurosci."},{"key":"1777_CR69","first-page":"51863","volume":"15","author":"JY Kim","year":"2014","unstructured":"Kim, J. Y., Grunke, S. D., Levites, Y., Golde, T. E. & Jankowsky, J. L. Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction. J. Vis. Exp. 15, 51863 (2014).","journal-title":"J. Vis. Exp."}],"container-title":["Nature Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41593-024-01777-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-024-01777-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41593-024-01777-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:04:21Z","timestamp":1773306261000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41593-024-01777-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,11]]},"references-count":69,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["1777"],"URL":"https:\/\/doi.org\/10.1038\/s41593-024-01777-2","relation":{},"ISSN":["1097-6256","1546-1726"],"issn-type":[{"value":"1097-6256","type":"print"},{"value":"1546-1726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,11]]},"assertion":[{"value":"21 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"H.Y.Z. cofounded Cajal Neuroscience, is a director of the Regeneron Pharmaceuticals board and is on the scientific advisory board of Cajal Neuroscience, Lyterian and the Column Group. D.M.H. cofounded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Cajal Neuroscience and Genentech, consults for Asteroid Therapeutics, is an inventor of and has a patent on antitau antibodies that was licensed by Washington University to C2N Diagnostics. B.H. owns stock in Novartis; he serves on the scientific advisory board of Dewpoint and has an option for stock. He serves on a scientific advisory board or is a consultant for AbbVie, Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZeneca, Biogen, BMS, Cure Alz Fund, Cell Signaling Technology, Dewpoint, Latus, Novartis, Pfizer, Sanofi, Sofinnova, Vigil, Violet, Voyager and WaveBreak. His laboratory is supported by research grants from the NIH, Cure Alzheimer\u2019s Fund, Tau Consortium and the JPB Foundation, as well as a sponsored research agreement from Abbvie. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}