1932

Abstract

The tauopathies constitute a group of diseases that have Tau inclusions in neurons or glia as their common denominator. In this review, we describe the biochemical and histological differences in Tau pathology that are characteristic of the spectrum of frontotemporal lobar degeneration as primary tauopathies and of Alzheimer's disease as a secondary tauopathy, as well as the commonalities and differences between the familial and sporadic forms. Furthermore, we discuss selected advances in transgenic animal models in delineating the different pathomechanisms of Tau.

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2019-01-24
2024-04-25
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Literature Cited

  1. 1.  Slomski A 2017. Tangled up in Tau. Proto 14:24–29
    [Google Scholar]
  2. 2.  Goedert M 2009. Oskar Fischer and the study of dementia. Brain 132:1102–11
    [Google Scholar]
  3. 3.  Kidd M 1963. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197:192–93
    [Google Scholar]
  4. 4.  Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI 1986. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. PNAS 83:4913–17
    [Google Scholar]
  5. 5.  Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM 1986. Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J. Biol. Chem. 261:6084–89
    [Google Scholar]
  6. 6.  Arriagada PV, Marzloff K, Hyman BT 1992. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology 42:1681–88
    [Google Scholar]
  7. 7.  Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT 1992. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42:631–39
    [Google Scholar]
  8. 8.  Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H et al. 2012. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71:362–81
    [Google Scholar]
  9. 9.  Braak H, Braak E 1995. Staging of Alzheimer's disease–related neurofibrillary changes. Neurobiol. Aging 16:271–78
    [Google Scholar]
  10. 10.  Cho H, Choi JY, Hwang MS, Kim YJ, Lee HM et al. 2016. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann. Neurol. 80:247–58
    [Google Scholar]
  11. 11.  Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M et al. 2016. PET imaging of tau deposition in the aging human brain. Neuron 89:971–82
    [Google Scholar]
  12. 12.  Arendt T, Stieler JT, Holzer M 2016. Tau and tauopathies. Brain Res. Bull. 126:238–92
    [Google Scholar]
  13. 13.  Koga S, Parks A, Kasanuki K, Sanchez-Contreras M, Baker MC et al. 2017. Cognitive impairment in progressive supranuclear palsy is associated with tau burden. Mov. Disord. 32:1772–79
    [Google Scholar]
  14. 14.  Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA 1989. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3:519–26
    [Google Scholar]
  15. 15.  Kosik KS, Finch EA 1987. MAP2 and tau segregate into dendritic and axonal domains after the elaboration of morphologically distinct neurites: an immunocytochemical study of cultured rat cerebrum. J. Neurosci. 7:3142–53
    [Google Scholar]
  16. 16.  Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A et al. 2010. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142:387–97
    [Google Scholar]
  17. 17.  Zempel H, Thies E, Mandelkow E, Mandelkow EM 2010. Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30:11938–50
    [Google Scholar]
  18. 18.  Sultan A, Nesslany F, Violet M, Begard S, Loyens A et al. 2011. Nuclear Tau, a key player in neuronal DNA protection. J. Biol. Chem. 286:4566–75
    [Google Scholar]
  19. 19.  Gunawardana CG, Mehrabian M, Wang X, Mueller I, Lubambo IB et al. 2015. The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (P301L) to chaperones and the proteasome. Mol. Cell. Proteom. 14:3000–14
    [Google Scholar]
  20. 20.  Multhaup G, Huber O, Buee L, Galas MC 2015. Amyloid precursor protein (APP) metabolites APP intracellular fragment (AICD), Aβ42, and Tau in nuclear roles. J. Biol. Chem. 290:23515–22
    [Google Scholar]
  21. 21.  Goedert M, Baur CP, Ahringer J, Jakes R, Hasegawa M et al. 1996. PTL-1, a microtubule-associated protein with tau-like repeats from the nematode Caenorhabditis elegans. J. Cell Sci 109:2661–72
    [Google Scholar]
  22. 22.  McDermott JB, Aamodt S, Aamodt E 1996. ptl-1, a Caenorhabditis elegans gene whose products are homologous to the τ microtubule-associated proteins. Biochemistry 35:9415–23
    [Google Scholar]
  23. 23.  Chew YL, Fan X, Götz J, Nicholas HR 2013. Protein with tau-like repeats regulates neuronal integrity and lifespan in C. elegans. J. . Cell Sci 126:2079–91
    [Google Scholar]
  24. 24.  Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K et al. 2015. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. PNAS 112:7501–6
    [Google Scholar]
  25. 25.  Bhaskar K, Yen SH, Lee G 2005. Disease-related modifications in tau affect the interaction between Fyn and tau. J. Biol. Chem. 280:35119–25
    [Google Scholar]
  26. 26.  Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K et al. 2004. Phosphorylation of tau by fyn: implications for Alzheimer's disease. J. Neurosci. 24:2304–12
    [Google Scholar]
  27. 27.  Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW et al. 2000. C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J. Cell Sci. 113:3737–45
    [Google Scholar]
  28. 28.  Flores-Rodriguez P, Ontiveros-Torres MA, Cardenas-Aguayo MC, Luna-Arias JP, Meraz-Rios MA et al. 2015. The relationship between truncation and phosphorylation at the C terminus of tau protein in the paired helical filaments of Alzheimer's disease. Front. Neurosci. 9:33
    [Google Scholar]
  29. 29.  Liu C, Song X, Nisbet R, Götz J 2016. Co-immunoprecipitation with Tau isoform–specific antibodies reveals distinct protein interactions, and highlights a putative role for 2N Tau in disease. J. Biol. Chem. 291:161–74
    [Google Scholar]
  30. 30.  Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A et al. 2015. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18:1183–89
    [Google Scholar]
  31. 31.  Li C, Götz J 2017. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat. Rev. Drug Disc. 16:863–83
    [Google Scholar]
  32. 32.  Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V et al. 2010. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67:953–66
    [Google Scholar]
  33. 33.  Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP et al. 2011. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2:252
    [Google Scholar]
  34. 34.  Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H et al. 2014. Proteopathic tau seeding predicts tauopathy in vivo. PNAS 111:E4376–85
    [Google Scholar]
  35. 35.  Mackenzie IR, Neumann M 2016. Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies. J. Neurochem. 138:Suppl. 154–70
    [Google Scholar]
  36. 36.  Odawara T, Iseki E, Kosaka K, Akiyama H, Ikeda K, Yamamoto T 1995. Investigation of tau-2 positive microglia-like cells in the subcortical nuclei of human neurodegenerative disorders. Neurosci. Lett. 192:145–48
    [Google Scholar]
  37. 37.  Komori T 1999. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Brain Pathol 9:663–79
    [Google Scholar]
  38. 38.  Pick A 1892. Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prag. Med. Wochenschr. 17:165–67
    [Google Scholar]
  39. 39.  Alzheimer A 1911. Über eigenartige Krankheitsfälle des späteren Alters. Z. Gesamte Neurol. Psychiatr. 4:356–85
    [Google Scholar]
  40. 40.  Joachim CL, Morris JH, Kosik KS, Selkoe DJ 1987. Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders. Ann. Neurol. 22:514–20
    [Google Scholar]
  41. 41.  Kato S, Nakamura H 1990. Presence of two different fibril subtypes in the Pick body: an immunoelectron microscopic study. Acta Neuropathol 81:125–29
    [Google Scholar]
  42. 42.  Murayama S, Mori H, Ihara Y, Tomonaga M 1990. Immunocytochemical and ultrastructural studies of Pick's disease. Ann. Neurol. 27:394–405
    [Google Scholar]
  43. 43.  Probst A, Tolnay M, Langui D, Goedert M, Spillantini MG 1996. Pick's disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment. Acta Neuropathol 92:588–96
    [Google Scholar]
  44. 44.  Yamazaki M, Nakano I, Imazu O, Kaieda R, Terashi A 1994. Astrocytic straight tubules in the brain of a patient with Pick's disease. Acta Neuropathol 88:587–91
    [Google Scholar]
  45. 45.  Ferrer I, Lopez-Gonzalez I, Carmona M, Arregui L, Dalfo E et al. 2014. Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J. Neuropathol. Exp. Neurol. 73:81–97
    [Google Scholar]
  46. 46.  Steele JC, Richardson JC, Olszewski J 1964. Progressive supranuclear palsy: a heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch. Neurol. 10:333–59
    [Google Scholar]
  47. 47.  Probst A, Langui D, Lautenschlager C, Ulrich J, Brion JP, Anderton BH 1988. Progressive supranuclear palsy: extensive neuropil threads in addition to neurofibrillary tangles: very similar antigenicity of subcortical neuronal pathology in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol 77:61–68
    [Google Scholar]
  48. 48.  Yamada T, McGeer PL, McGeer EG 1992. Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci. Lett. 135:99–102
    [Google Scholar]
  49. 49.  Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K et al. 1994. Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–19
    [Google Scholar]
  50. 50.  Nishimura T, Ikeda K, Akiyama H, Kondo H, Kato M et al. 1995. Immunohistochemical investigation of tau-positive structures in the cerebral cortex of patients with progressive supranuclear palsy. Neurosci. Lett. 201:123–26
    [Google Scholar]
  51. 51.  Dickson DW, Yen SH, Suzuki KI, Davies P, Garcia JH, Hirano A 1986. Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes. Acta Neuropathol 71:216–23
    [Google Scholar]
  52. 52.  Halliday GM, Davies L, McRitchie DA, Cartwright H, Pamphlett R, Morris JG 1995. Ubiquitin-positive achromatic neurons in corticobasal degeneration. Acta Neuropathol 90:68–75
    [Google Scholar]
  53. 53.  Uchihara T, Mitani K, Mori H, Kondo H, Yamada M, Ikeda K 1994. Abnormal cytoskeletal pathology peculiar to corticobasal degeneration is different from that of Alzheimer's disease or progressive supranuclear palsy. Acta Neuropathol 88:379–83
    [Google Scholar]
  54. 54.  Komori T, Arai N, Oda M, Nakayama H, Mori H et al. 1998. Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 96:401–8
    [Google Scholar]
  55. 55.  Dickson DW 1999. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J. Neurol. 246:Suppl. 2II6–15
    [Google Scholar]
  56. 56.  Bigio EH, Lipton AM, Yen SH, Hutton ML, Baker M et al. 2001. Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia. J. Neuropathol. Exp. Neurol. 60:328–41
    [Google Scholar]
  57. 57.  Kovacs GG, Majtenyi K, Spina S, Murrell JR, Gelpi E et al. 2008. White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J. Neuropathol. Exp. Neurol. 67:963–75
    [Google Scholar]
  58. 58.  Ahmed Z, Doherty KM, Silveira-Moriyama L, Bandopadhyay R, Lashley T et al. 2011. Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies. Acta Neuropathol 122:415–28
    [Google Scholar]
  59. 59.  Ahmed Z, Bigio EH, Budka H, Dickson DW, Ferrer I et al. 2013. Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–44
    [Google Scholar]
  60. 60.  Ikeda K, Akiyama H, Kondo H, Haga C 1995. A study of dementia with argyrophilic grains: possible cytoskeletal abnormality in dendrospinal portion of neurons and oligodendroglia. Acta Neuropathol 89:409–14
    [Google Scholar]
  61. 61.  Braak H, Braak E 1987. Argyrophilic grains: characteristic pathology of cerebral cortex in cases of adult onset dementia without Alzheimer changes. Neurosci. Lett. 76:124–27
    [Google Scholar]
  62. 62.  Braak H, Braak E 1989. Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol. Appl. Neurobiol. 15:13–26
    [Google Scholar]
  63. 63.  Tolnay M, Spillantini MG, Goedert M, Ulrich J, Langui D, Probst A 1997. Argyrophilic grain disease: widespread hyperphosphorylation of tau protein in limbic neurons. Acta Neuropathol 93:477–84
    [Google Scholar]
  64. 64.  Grinberg LT, Wang X, Wang C, Sohn PD, Theofilas P et al. 2013. Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581–93
    [Google Scholar]
  65. 65.  Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S et al. 1998. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–5
    [Google Scholar]
  66. 66.  Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM et al. 1998. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43:815–25
    [Google Scholar]
  67. 67.  Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B 1998. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. PNAS 95:7737–41
    [Google Scholar]
  68. 68.  Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M et al. 2018. Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 141:521–34
    [Google Scholar]
  69. 69.  Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM et al. 2007. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22
    [Google Scholar]
  70. 70.  Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P et al. 2016. Preclinical Alzheimer's disease: definition, natural history, and diagnostic criteria. Alzheimer's Dement 12:292–323
    [Google Scholar]
  71. 71.  Jellinger KA, Attems J 2015. Challenges of multimorbidity of the aging brain: a critical update. J. Neural Transm. 122:505–21
    [Google Scholar]
  72. 72.  Van der Flier WM 2016. Clinical heterogeneity in familial Alzheimer's disease. Lancet Neurol 15:1296–98
    [Google Scholar]
  73. 73.  Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G et al. 2005. A common inversion under selection in Europeans. Nat. Genet. 37:129–37
    [Google Scholar]
  74. 74.  Lai MC, Bechy AL, Denk F, Collins E, Gavriliouk M et al. 2017. Haplotype-specific MAPT exon 3 expression regulated by common intronic polymorphisms associated with Parkinsonian disorders. Mol. Neurodegener. 12:79
    [Google Scholar]
  75. 75.  Caffrey TM, Joachim C, Paracchini S, Esiri MM, Wade-Martins R 2006. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15:3529–37
    [Google Scholar]
  76. 76.  Caffrey TM, Joachim C, Wade-Martins R 2008. Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol. Aging 29:1923–29
    [Google Scholar]
  77. 77.  McCarthy A, Lonergan R, Olszewska DA, O'Dowd S, Cummins G et al. 2015. Closing the tau loop: the missing tau mutation. Brain 138:3100–9
    [Google Scholar]
  78. 78.  Lacovich V, Espindola SL, Alloatti M, Pozo Devoto V, Cromberg LE et al. 2017. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J. Neurosci. 37:58–69
    [Google Scholar]
  79. 79.  Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T et al. 2017. Altered tau isoform ratio caused by loss of FUS and SFPQ function leads to FTLD-like phenotypes. Cell Rep 18:1118–31
    [Google Scholar]
  80. 80.  Hasegawa M, Smith MJ, Goedert M 1998. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–10
    [Google Scholar]
  81. 81.  Nacharaju P, Lewis J, Easson C, Yen S, Hackett J et al. 1999. Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 447:195–99
    [Google Scholar]
  82. 82.  Alonso Adel C, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K 2004. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279:34873–81
    [Google Scholar]
  83. 83.  Gauthier A, Brandt R 2010. Live cell imaging of cytoskeletal dynamics in neurons using fluorescence photoactivation. Biol. Chem. 391:639–43
    [Google Scholar]
  84. 84.  Connell JW, Gibb GM, Betts JC, Blackstock WP, Gallo J et al. 2001. Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by glycogen synthase kinase 3β identified by mass spectrometry demonstrate certain mutations exert long-range conformational changes. FEBS Lett 493:40–44
    [Google Scholar]
  85. 85.  Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E 2006. Global hairpin folding of tau in solution. Biochemistry 45:2283–93
    [Google Scholar]
  86. 86.  Rasmussen J, Mahler J, Beschorner N, Kaeser SA, Hasler LM et al. 2017. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. PNAS 114:13018–23
    [Google Scholar]
  87. 87.  Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Götz J 2018. Amyloid-β and tau complexity—towards improved biomarkers and targeted therapies. Nat. Rev. Neurol. 14:22–39
    [Google Scholar]
  88. 88.  Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S et al. 2013. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. PNAS 110:9535–40
    [Google Scholar]
  89. 89.  Polanco JC, Scicluna BJ, Hill AF, Götz J 2016. Extracellular vesicles isolated from the brains of rTg4510 mice seed tau protein aggregation in a threshold-dependent manner. J. Biol. Chem. 291:12445–66
    [Google Scholar]
  90. 90.  Xia D, Gutmann JM, Götz J 2016. Mobility and subcellular localization of endogenous, gene-edited Tau differs from that of over-expressed human wild-type and P301L mutant Tau. Sci. Rep. 6:29074
    [Google Scholar]
  91. 91.  Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T et al. 2017. APP mouse models for Alzheimer's disease preclinical studies. EMBO J 36:2473–87
    [Google Scholar]
  92. 92.  van Hummel A, Bi M, Ippati S, van der Hoven J, Volkerling A et al. 2016. No overt deficits in aged tau-deficient C57Bl/6.Mapttm1(EGFP)Kit GFP knockin mice. PLOS ONE 11:e0163236
    [Google Scholar]
  93. 93.  Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ et al. 2014. Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris Water Maze with aging. J. Neurosci. 34:7124–36
    [Google Scholar]
  94. 94.  Gilley J, Seereeram A, Ando K, Mosely S, Andrews S et al. 2012. Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a “P301L” tau knockin mouse. Neurobiol. Aging 33:621.e1–621.e15
    [Google Scholar]
  95. 95.  Dujardin S, Colin M, Buee L 2015. Animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol. Appl. Neurobiol. 41:59–80
    [Google Scholar]
  96. 96.  Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G et al. 2017. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature 547:185–90
    [Google Scholar]
  97. 97.  Takashima A 2013. Tauopathies and tau oligomers. J. Alzheimer's Dis. 37:565–68
    [Google Scholar]
  98. 98.  Ittner LM, Fath T, Ke YD, Bi M, van Eersel J et al. 2008. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. PNAS 105:15997–6002
    [Google Scholar]
  99. 99.  Ittner LM, Ke YD, Götz J 2009. Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J. Biol. Chem. 284:20909–16
    [Google Scholar]
  100. 100.  Grimm A, Friedland K, Eckert A 2016. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease. Biogerontology 17:281–96
    [Google Scholar]
  101. 101.  Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P 2005. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. 25:5446–54
    [Google Scholar]
  102. 102.  Seward ME, Swanson E, Norambuena A, Reimann A, Cochran JN et al. 2013. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J. Cell Sci. 126:1278–86
    [Google Scholar]
  103. 103.  Khurana V, Merlo P, Duboff B, Fulga TA, Sharp KA et al. 2012. A neuroprotective role for the DNA damage checkpoint in tauopathy. Aging Cell 11:360–62
    [Google Scholar]
  104. 104.  Frost B, Hemberg M, Lewis J, Feany MB 2014. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17:357–66
    [Google Scholar]
  105. 105.  Frost B, Bardai FH, Feany MB 2016. Lamin dysfunction mediates neurodegeneration in tauopathies. Curr. Biol. 26:129–36
    [Google Scholar]
  106. 106.  Dalby NO, Volbracht C, Helboe L, Larsen PH, Jensen HS et al. 2014. Altered function of hippocampal CA1 pyramidal neurons in the rTg4510 mouse model of tauopathy. J. Alzheimer's Dis. 40:429–42
    [Google Scholar]
  107. 107.  Kopeikina KJ, Wegmann S, Pitstick R, Carlson GA, Bacskai BJ et al. 2013. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLOS ONE 8:e80834
    [Google Scholar]
  108. 108.  Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA et al. 2010. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–81
    [Google Scholar]
  109. 109.  Xia D, Li C, Götz J 2015. Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines. Biochim. Biophys. Acta 1852:913–24
    [Google Scholar]
  110. 110.  Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH et al. 2007. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316:750–54
    [Google Scholar]
  111. 111.  DeVos SL, Goncharoff DK, Chen G, Kebodeaux CS, Yamada K et al. 2013. Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33:12887–97
    [Google Scholar]
  112. 112.  Holth JK, Bomben VC, Reed JG, Inoue T, Younkin L et al. 2013. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33:1651–59
    [Google Scholar]
  113. 113.  Crimins JL, Rocher AB, Luebke JI 2012. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol 124:777–95
    [Google Scholar]
  114. 114.  Hatch RJ, Wei Y, Xia D, Götz J 2017. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol 133:717–30
    [Google Scholar]
  115. 115.  Bloom GS 2014. Amyloid-β and Tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505–8
    [Google Scholar]
  116. 116.  Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N et al. 2005. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 25:9694–703
    [Google Scholar]
  117. 117.  Chin J, Palop JJ, Yu GQ, Kojima N, Masliah E, Mucke L 2004. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J. Neurosci. 24:4692–97
    [Google Scholar]
  118. 118.  Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA et al. 2015. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann. Neurol. 77:953–71
    [Google Scholar]
  119. 119.  Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA et al. 2012. The complex PrPc–Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J. Neurosci. 32:16857–71
    [Google Scholar]
  120. 120.  Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M et al. 2013. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79:887–902
    [Google Scholar]
  121. 121.  Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M et al. 2012. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15:1227–35
    [Google Scholar]
  122. 122.  Usardi A, Pooler AM, Seereeram A, Reynolds CH, Derkinderen P et al. 2011. Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J 278:2927–37
    [Google Scholar]
  123. 123.  Ittner LM, Götz J 2011. Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease. Nat. Rev. Neurosci. 12:65–72
    [Google Scholar]
  124. 124.  Haass C, Mandelkow E 2010. Fyn-tau-amyloid: a toxic triad. Cell 142:356–58
    [Google Scholar]
  125. 125.  Li X, Kumar Y, Zempel H, Mandelkow EM, Biernat J, Mandelkow E 2011. Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration. EMBO J 30:4825–37
    [Google Scholar]
  126. 126.  Li C, Götz J 2017. Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn-mediated local protein translation. EMBO J 36:3120–38
    [Google Scholar]
  127. 127.  Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A et al. 2004. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 61:95–102
    [Google Scholar]
  128. 128.  Olsson A, Vanderstichele H, Andreasen N, De Meyer G, Wallin A et al. 2005. Simultaneous measurement of β-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin. Chem. 51:336–45
    [Google Scholar]
  129. 129.  White R, Gonsior C, Kramer-Albers EM, Stohr N, Huttelmaier S, Trotter J 2008. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2–dependent RNA granules. J. Cell Biol. 181:579–86
    [Google Scholar]
  130. 130.  Kramer-Albers EM, White R 2011. From axon-glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase. Cell. Mol. Life Sci. 68:2003–12
    [Google Scholar]
  131. 131.  Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H et al. 1993. Constitutive activation of Src family kinases in mouse embryos that lack Csk. Cell 73:1125–35
    [Google Scholar]
  132. 132.  Xu J, Kurup P, Foscue E, Lombroso PJ 2015. Striatal-enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway. J. Neurochem. 134:629–41
    [Google Scholar]
  133. 133.  Roskoski R Jr 2004. Src protein–tyrosine kinase structure and regulation. Biochem. Biophys. Res. Commun. 324:1155–64
    [Google Scholar]
  134. 134.  Ostareck-Lederer A, Ostareck DH, Cans C, Neubauer G, Bomsztyk K et al. 2002. c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs. Mol. Cell. Biol. 22:4535–43
    [Google Scholar]
  135. 135.  Sette C, Paronetto MP, Barchi M, Bevilacqua A, Geremia R, Rossi P 2002. Tr-kit-induced resumption of the cell cycle in mouse eggs requires activation of a Src-like kinase. EMBO J 21:5386–95
    [Google Scholar]
  136. 136.  Salazar SV, Strittmatter SM 2017. Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease. Biochem. Biophys. Res. Commun. 483:1143–47
    [Google Scholar]
  137. 137.  Huang Y, Lu W, Ali DW, Pelkey KA, Pitcher GM et al. 2001. CAKβ/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron 29:485–96
    [Google Scholar]
  138. 138.  Collins MO, Husi H, Yu L, Brandon JM, Anderson CN et al. 2006. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J. Neurochem. 97:Suppl. 116–23
    [Google Scholar]
  139. 139.  Lakkakorpi PT, Bett AJ, Lipfert L, Rodan GA, Duong LT 2003. PYK2 autophosphorylation, but not kinase activity, is necessary for adhesion-induced association with c-Src, osteoclast spreading, and bone resorption. J. Biol. Chem. 278:11502–12
    [Google Scholar]
  140. 140.  Zhang Z, Zhang Y, Mou Z, Chu S, Chen X et al. 2014. Tyrosine 402 phosphorylation of Pyk2 is involved in ionomycin-induced neurotransmitter release. PLOS ONE 9:e94574
    [Google Scholar]
  141. 141.  Xu J, Kurup P, Nairn AC, Lombroso PJ 2012. Striatal-enriched protein tyrosine phosphatase in Alzheimer's disease. Adv. Pharmacol. 64:303–25
    [Google Scholar]
  142. 142.  Dourlen P, Fernandez-Gomez FJ, Dupont C, Grenier-Boley B, Bellenguez C et al. 2017. Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. Mol. Psychiatry 22:874–83
    [Google Scholar]
  143. 143.  Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R et al. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45:1452–58
    [Google Scholar]
  144. 144.  De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC et al. 2014. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat. Neurosci 17:1156–63
    [Google Scholar]
  145. 145.  Chan G, White CC, Winn PA, Cimpean M, Replogle JM et al. 2015. CD33 modulates TREM2: convergence of Alzheimer loci. Nat. Neurosci. 18:1556–58
    [Google Scholar]
  146. 146.  Köhler C, Dinekov M, Götz J 2013. Active glycogen synthase kinase-3 and tau pathology–related tyrosine phosphorylation in pR5 human tau transgenic mice. Neurobiol. Aging 34:1369–79
    [Google Scholar]
  147. 147.  Li C, Götz J 2018. Pyk2 is a novel tau tyrosine kinase that is regulated by the tyrosine kinase Fyn. J. Alzheimer's Dis. 65:205–21
    [Google Scholar]
  148. 148.  Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E 2011. Alzheimer's disease. Lancet 377:1019–31
    [Google Scholar]
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