Lee VM-Y, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. https://doi.org/10.1146/annurev.neuro.24.1.1121

Article  CAS  PubMed  Google Scholar 

Gómez-Isla T, Price JL, McKeel DW, Morris JC, Growdon JH, Hyman BT (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500. https://doi.org/10.1523/jneurosci.16-14-04491.1996

Article  PubMed  PubMed Central  Google Scholar 

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259. https://doi.org/10.1007/BF00308809

Article  CAS  PubMed  Google Scholar 

Sato S, Cerny RL, Buescher JL, Ikezu T (2006) Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation. J Neurochem 98:1573–1584. https://doi.org/10.1111/j.1471-4159.2006.04059.x

Article  CAS  PubMed  Google Scholar 

Lund H, Cowburn RF, Gustafsson E, Strömberg K, Svensson A, Dahllund L, Malinowsky D, Sunnemark D (2013) Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer’s disease brain. Brain Pathol 23:378–389. https://doi.org/10.1111/bpa.12001

Article  CAS  PubMed  Google Scholar 

Ikezu S, Dixie KLI, Koro L, Watanabe T, Kaibuchi K (2020) Tau-tublin kinase 1 and amyloid-beta peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models. Acta Neuropathol Commun 4:1–16

Google Scholar 

Sato S, Xu J, Okuyama S, Martinez LB, Walsh SM, Jacobsen MT, Swan RJ, Schlautman JD, Ciborowski P, Ikezu T (2008) Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. J Neurosci 28:14511–14521. https://doi.org/10.1523/JNEUROSCI.3417-08.2008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu J, Sato S, Okuyama S, Swan RJ, Jacobsen MT, Strunk E, Ikezu T (2010) Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice. FASEB J 24:2904–2915. https://doi.org/10.1096/fj.09-150144

Article  CAS  PubMed  Google Scholar 

Kimura T, Ono T, Takamatsu J, Yamamoto H, Ikegami K, Kondo A, Hasegawa M, Ihara Y, Miyamoto E, Miyakawa T (1996) Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dement Geriatr Cogn Disord 7:177–181. https://doi.org/10.1159/000106875

Article  CAS  Google Scholar 

Cavallini A, Brewerton S, Bell A, Sargent S, Glover S, Hardy C, Moore R, Calley J, Ramachandran D, Poidinger M et al (2013) An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with alzheimer disease. J Biol Chem 288:23331–23347. https://doi.org/10.1074/jbc.M113.463984

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moloney CM, Labuzan SA, Crook JE, Siddiqui H, Castanedes-Casey M, Lachner C, Petersen RC, Duara R, Graff-Radford NR, Dickson DW et al (2022) Phosphorylated tau sites that are elevated in Alzheimer’s disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the post mortem brain. Alzheimer’s Dement. https://doi.org/10.1002/alz.12749

Article  Google Scholar 

Aragão Gomes L, Uytterhoeven V, Lopez-Sanmartin D, Tomé SO, Tousseyn T, Vandenberghe R, Vandenbulcke M, von Arnim CAF, Verstreken P, Thal DR (2021) Maturation of neuronal AD-tau pathology involves site-specific phosphorylation of cytoplasmic and synaptic tau preceding conformational change and fibril formation. Acta Neuropathol. 141:173–192. https://doi.org/10.1007/s00401-020-02251-6

Article  CAS  PubMed  Google Scholar 

Yu NN, Yu JT, Xiao JT, Zhang HW, Lu RC, Jiang H, Xing ZH, Tan L (2011) Tau-tubulin kinase-1 gene variants are associated with Alzheimer’s disease in Han Chinese. Neurosci Lett 491:83–86. https://doi.org/10.1016/j.neulet.2011.01.011

Article  CAS  PubMed  Google Scholar 

Vázquez-Higuera JL, Mateo I, Sánchez-Juan P, Rodríguez-Rodríguez E, Pozueta A, Calero M, Dobato JL, Frank-García A, Valdivieso F, Berciano J et al (2011) Genetic variation in the tau kinases pathway may modify the risk and age at onset of Alzheimer’s disease. J Alzheimer’s Dis 27:291–297. https://doi.org/10.3233/JAD-2011-110794

Article  CAS  Google Scholar 

Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, Gattis D, Hung G, Kordasiewicz HB, Paulson HL, McLoughlin HS (2017) Evaluation of antisense oligonucleotides targeting ATXN3 in SCA3 mouse models. Mol Ther Nucleic Acids 7:200–210. https://doi.org/10.1016/j.omtn.2017.04.005

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TCC, Maeda J, Suhara T, Trojanowski JQ, Lee VMY (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. https://doi.org/10.1016/j.neuron.2007.01.010

Article  CAS  PubMed  Google Scholar 

Sahara N, Lewis J, DeTure M, McGowan E, Dickson DW, Hutton M, Yen SH (2002) Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility. J Neurochem 83:1498–1508. https://doi.org/10.1046/j.1471-4159.2002.01241.x

Article  CAS  PubMed  Google Scholar 

Cuny G (2009) Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr Pharm Des 15:3919–3939. https://doi.org/10.2174/138161209789649330

Article  CAS  PubMed  Google Scholar 

Tiernan CT, Combs B, Cox K, Morfini G, Brady ST, Counts SE, Kanaan NM (2016) Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport. Exp Neurol 283:318–329. https://doi.org/10.1016/j.expneurol.2016.06.030

Article  CAS  PubMed  PubMed Central  Google Scholar 

Planel E, Richter KEG, Nolan CE, Finley JE, Liu L, Wen Y, Krishnamurthy P, Herman M, Wang L, Schachter JB et al (2007) Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci 27:3090–3097. https://doi.org/10.1523/JNEUROSCI.4854-06.2007

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–527. https://doi.org/10.1038/nature24016

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ruan Z, Pathak D, Venkatesan Kalavai S, Yoshii-Kitahara A, Muraoka S, Bhatt N, Takamatsu-Yukawa K, Hu J, Wang Y, Hersh S et al (2021) Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain 144:288–309. https://doi.org/10.1093/brain/awaa376

Article  PubMed  Google Scholar 

Kohnken R, Buerger K, Zinkowski R, Miller C, Kerkman D, DeBernardis J, Shen J, Möller H-J, Davies P, Hampel H (2000) Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer’s disease patients. Neurosci Lett 287:187–190. https://doi.org/10.1016/S0304-3940(00)01178-2

Article  CAS  PubMed  Google Scholar 

Vanmechelen E, Vanderstichele H, Davidsson P, Van Kerschaver E, Van Der Perre B, Sjögren M, Andreasen N, Blennow K (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285:49–52. https://doi.org/10.1016/S0304-3940(00)01036-3

Article  CAS  PubMed  Google Scholar 

Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O’Loughlin E, Xu Y, Fanek Z et al (2017) The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566-581.e9. https://doi.org/10.1016/j.immuni.2017.08.008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P, Singleton AB, Hilton DA, Holton J, Revesz T et al (2007) Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39:1434–1436. https://doi.org/10.1038/ng.2007.43

Article  CAS  PubMed  Google Scholar 

Wang J-Z, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68. https://doi.org/10.1111/j.1460-9568.2006.05226.x

Article  PubMed  PubMed Central  Google Scholar 

Halkina T, Henderson JL, Lin EY, Himmelbauer MK, Jones JH, Nevalainen M, Feng J, King K, Rooney M, Johnson JL et al (2021) Discovery of potent and brain-penetrant tau tubulin kinase 1 (TTBK1) inhibitors that lower tau phosphorylation in vivo. J Med Chem 64:6358–6380. https://doi.org/10.1021/acs.jmedchem.1c00382

Article  CAS  PubMed  Google Scholar 

Dillon GM, Henderson JL, Bao C, Joyce JA, Calhoun M, Amaral B, King KW, Bajrami B, Rabah D (2020) Acute inhibition of the CNS-specific kinase TTBK1 significantly lowers tau phosphorylation at several disease relevant sites. PLoS ONE 15:1–22. https://doi.org/10.1371/journal.pone.0228771

Article  CAS  Google Scholar 

Marcotte DJ, Spilker KA, Wen D, Hesson T, Patterson TA, Kumar PR, Chodaparambil JV (2020) The crystal structure of the catalytic domain of tau tubulin kinase 2 in complex with a small-molecule inhibitor. Acta Crystallogr Sect F Struct Biol Commun 76:103–108. https://doi.org/10.1107/S2053230X2000031X

Article  CAS  Google Scholar 

Jana S, Singh SK (2020) Identification of human tau-tubulin kinase 1 inhibitors: an integrated e-pharmacophore-based virtual screening and molecular dynamics simulation. J Biomol Struct Dyn 38:886–900. https://doi.org/10.1080/07391102.2019.1590242