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The Biology and Pathobiology of Tau Protein

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Cytoskeleton and Human Disease

Abstract

The cytoskeleton-associated protein tau has a remarkably varied repertory of cellular functions in neurons in both health and disease. Although tau is classically thought of as a neuronal phosphoprotein that stabilizes axonal microtubules (MTs), it interacts with diverse signaling pathways via proteins in the cortical cytoskeleton as well and plays important roles in several aspects of axonal development and function. Abnormalities in non-MT-associated functions of tau are increasingly thought to be involved in the pathogenesis of neurodegenerative disease in humans, which is the focus of this monograph. I will first summarize normal tau interactions with other proteins and cellular functions as we currently understand them in the context of tau structure and expression patterns and discuss how these are altered in the context of neurodegenerative disease at the molecular, cellular, and organismal levels. Particular attention is given to recent studies of the cellular and intercellular aspects of tau misprocessing and their implications for the pathogenesis of human neurodegenerative disease.

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References

  1. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Nat Acad Sci 72:1858–1862

    Article  PubMed  CAS  Google Scholar 

  2. Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247

    Article  PubMed  CAS  Google Scholar 

  3. Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116:207–225

    Article  PubMed  CAS  Google Scholar 

  4. Drechsel DN, Hyman AA, Cobb MH, Kirschner MW (1992) Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 3:1141–1154

    PubMed  CAS  Google Scholar 

  5. Chen JY, Kanai N, Cowan J, Hirokawa N (1992) Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons. Nature (Lond) 360:674–677

    Article  CAS  Google Scholar 

  6. Ennulat DJ, Liem RK, Hashim GA, Shelanski ML (1989) Two separate 18-amino acid domains of tau promote the polymerization of tubulin. J Biol Chem 264: 5327–5330

    PubMed  CAS  Google Scholar 

  7. Lee G, Neve RL, Kosik KS (1989) The microtubule binding domain of tau protein. Neuron 2:1615–1624

    Article  PubMed  CAS  Google Scholar 

  8. Lindwall G, Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259:5301–5305

    PubMed  CAS  Google Scholar 

  9. Papasozomenos SC, Binder LI (1987) Phosphorylation determines two distinct species of tau in the central nervous system. Cell Motil Cytoskel 8:210–226

    Article  CAS  Google Scholar 

  10. McDermott JB, Aamodt S, Aamodt E (1996) ptl-1, a Caenorhabditis elegans gene whose products are homologous to the tau microtubule-associated proteins. Biochemistry 35:9415–9423

    Article  PubMed  CAS  Google Scholar 

  11. Heidary G, Fortini ME (2001) Identification and characterization of the Drosophila tau homolog. Mech Dev 108:171–178

    Article  PubMed  CAS  Google Scholar 

  12. Dehmel L, Halpain S (2004) The MAP2/Tau family of microtubule-associated proteins. Genome Biology 6:204–216

    Article  Google Scholar 

  13. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau polypeptides in the mammalian central nervous system. J Cell Biol 101:1371–1378

    Article  PubMed  CAS  Google Scholar 

  14. Matus A, Bernhardt R, Hugh-Jones T (1981) High-molecular weight microtubule-associated proteins are preferentially associated with dendritic microtubules in brain. Proc Natl Acad Sci USA 78:3010–3014

    Article  PubMed  CAS  Google Scholar 

  15. Nelson PT, Stefansson K, Gulcher J, Saper CB (1996) Molecular evolution of tau protein: implications for Alzheimer’s disease. J Neurochem 67:1622–1632

    Article  PubMed  CAS  Google Scholar 

  16. Goedert M, Baur CP, Ahringer J, Jakes R, Hasegawa M, Spillantini MG, Smith MJ, Hill F (1996) PTL-1, a microtubule-associated protein with tau-like repeats from the nematode Caenorhabditis elegans. J Cell Sci 109:2661–2672

    PubMed  CAS  Google Scholar 

  17. Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM. Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H (2004) Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J Neurosci 24:2304–2312

    Article  PubMed  CAS  Google Scholar 

  18. King M (2005) Can tau filaments be both physiologically beneficial and toxic? Biochim Biophys Acta 739:260–267

    Google Scholar 

  19. Andreadis A (2005) Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta 1739:91–103

    Article  PubMed  CAS  Google Scholar 

  20. Luo MH, Tse SW, Memmott J, Andreadis A (2004) Novel isoforms of tau that lack the microtubule-binding domain. J Neurochem 90:340–351

    Article  PubMed  CAS  Google Scholar 

  21. Loomis PA, Howard TH, Castleberry RP, Binder L (1990) Identification of nuclear tau isoforms in human neuroblastoma cells. Proc Natl Acad Sci USA 87:8422–8426

    Article  PubMed  CAS  Google Scholar 

  22. Cross DC, Muñoz JP, Hernández P, Maccioni RB (2000) Nuclear and cytoplasmic tau proteins from human nonneuronal cells share common structural and functional features with brain tau. J Cell Biochem 78(2):305–317

    Article  PubMed  CAS  Google Scholar 

  23. Caceres A, Kosik KS (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343:461–463

    Article  PubMed  CAS  Google Scholar 

  24. Caceres A, Mautino J, Kosik KS (1992) Suppression of MAP2 in cultured cerebellar macroneurons inhibits minor neurite formation. Neuron 9:607–618

    Article  PubMed  CAS  Google Scholar 

  25. Dotti CG, Sullivan CA, Banker GA (1988) The establishment of polarity by hippocampal neurons in culture. J Neurosci 8:1454–1468

    PubMed  CAS  Google Scholar 

  26. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van Der Zee EA et al (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23:6972–6981

    PubMed  CAS  Google Scholar 

  27. Cantero J, Hita-Yanez E, Moreno-Lopez B, Portillo F, Rubio A, Avila J (2010) Tau protein role in sleep-wake cycle. J Alz Dis 21:411–421

    CAS  Google Scholar 

  28. Mukrasch MD, von Bergen M, Biernat J, Fischer D, Griesinger C, Mandelkow E, Zweckstetter M (2007) The “jaws” of the tau-microtubule interaction. J Biol Chem 282:12230–12239

    Article  PubMed  CAS  Google Scholar 

  29. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739:216–223

    Article  PubMed  CAS  Google Scholar 

  30. Iliev AI, Ganesan S, Bunt G, Wouters FS (2006) Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity. J Biol Chem 281:37195–37204

    Article  PubMed  CAS  Google Scholar 

  31. Butner KA, Kirschner MW (1991) Tau protein binds to microtubules through a flexible array of distributed weak sites. J Cell Biol 115:717–730

    Article  PubMed  CAS  Google Scholar 

  32. Al-Bassam J, Ozer RS, Safer D, Halpain S, Milligan RA (2002) MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments. J Cell Biol 157:1187–1196

    Article  PubMed  CAS  Google Scholar 

  33. Samsonov A, Yu JZ, Rasenick M, Popov SV (2004) Tau interaction with microtubules in vivo. J Cell Sci 117:6129–6141

    Article  PubMed  CAS  Google Scholar 

  34. Makrides V, Massie MR, Feinstein SC, Lew J (2004) Evidence for two distinct binding sites for tau on microtubules. Proc Natl Acad Sci USA 101:6746–6751

    Article  PubMed  CAS  Google Scholar 

  35. Goode BL, Chau M, Denis PE, Feinstein SC (2000) Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenerative disease. J Biol Chem 275:38182–38189

    Article  PubMed  CAS  Google Scholar 

  36. Panda D, Samuel JC, Massie M, Feinstein SC, Wilson L (2003) Differential regulation of microtubule dynamics by three- and four repeat tau: implications for the onset of neurodegenerative disease. Proc Natl Acad Sci USA 100:9548–9553

    Article  PubMed  CAS  Google Scholar 

  37. Felgner H, Frank R, Biernat J, Mandelkow EM, Mandelkow E, Ludin B, Matus A, Schliwa M (1997) Domains of neuronal microtubule-associated proteins and flexural rigidity of microtubules. J Cell Biol 138:1067–1075

    Article  PubMed  CAS  Google Scholar 

  38. Hagestedt T, Lichtenberg B, Wille H, Mandelkow EM, Mandelkow E (1989) Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. J Cell Biol 109:1643–1651

    Article  PubMed  CAS  Google Scholar 

  39. Rissman RA, Lee KF, Vale W, Sawchenko PE (2007) Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation. J Neurosci 27:6552–6562

    Article  PubMed  CAS  Google Scholar 

  40. Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S et al (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer’s disease. J Neurosci 24:2401–2411

    Article  PubMed  CAS  Google Scholar 

  41. Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68

    Article  PubMed  Google Scholar 

  42. Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 83:4044–4048

    Article  PubMed  CAS  Google Scholar 

  43. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917

    Article  PubMed  CAS  Google Scholar 

  44. Avila J (2006) Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett 580:2922–2927

    Article  PubMed  CAS  Google Scholar 

  45. Stoothoff W, Johnson GV (2005) Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 1739:280–297

    Article  PubMed  CAS  Google Scholar 

  46. Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11:153–163

    Article  PubMed  CAS  Google Scholar 

  47. Ishiguro K, Shiratsuchi A, Sato S, Omori A, Arioka M, Kobayashi S et al (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325:167–172

    Article  PubMed  CAS  Google Scholar 

  48. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995

    Article  PubMed  CAS  Google Scholar 

  49. Hernandez F, Perez M, Lucas JJ, Mata AM, Bhat R, Avila J (2004) Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer’s disease. J Biol Chem 279:3801–3806

    Article  PubMed  CAS  Google Scholar 

  50. Pei JJ, Grundke-Iqbal I, Iqbal K, Bogdanovic N, Winblad B, Cowburn RF (1998) Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer’s disease neurofibrillary degeneration. Brain Res 797:267–277

    Article  PubMed  CAS  Google Scholar 

  51. Pei JJ, Bjorkdahl C, Zhang H, Zhou X, Winblad B (2008) p70 S6 Kinase and Tau in Alzheimer’s Disease. J Alz Dis 14:385–392

    Google Scholar 

  52. Baumann K et al (1993) Abnormal Alzheimerlike phosphorylation of Tau-protein by cyclin dependent kinases Cdk2 and Cdk5. FEBS Lett 336:417–424

    Article  PubMed  CAS  Google Scholar 

  53. Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89:297–308

    Article  PubMed  CAS  Google Scholar 

  54. Sengupta A, Wu Q, Grundke-Iqbal I, Iqbal K, Singh TJ (1997) Potentiation of GSK-3 catalyzed Alzheimer-like phosphorylation of human tau by Cdk5. Mol Cell Biochem 167:99–105

    Article  PubMed  CAS  Google Scholar 

  55. Schneider A, Biernat J, Von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38:3549–3558

    Article  PubMed  CAS  Google Scholar 

  56. Biernat J, Mandelkow EM (1999) The development of cell processes induced by tau protein requires phosphorylation of Serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains. Mol Biol Cell 10:727–740

    PubMed  CAS  Google Scholar 

  57. Biernat J et al (2002) Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 13:4013–4028

    Article  PubMed  CAS  Google Scholar 

  58. Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K et al (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells 10:165–179

    Article  PubMed  CAS  Google Scholar 

  59. Asuni AA, Hooper C, Reynolds CH, Lovestone S, Anderton BH, Killick R (2006) GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur J Neurosci 24:3387–3392

    Article  PubMed  Google Scholar 

  60. Pope WB, Lambert MP, Leypold B, Seupaul R, Sletten, L, Krafft G, Klein WL (1994) Microtubule-associated protein tau is hyperphosphorylated during mitosis in the human neuroblastoma cell line SH-SY5Y. Exp Neurol 126:185–194

    Article  PubMed  CAS  Google Scholar 

  61. Arendt T, Holzer M, Grossmann A, Zedlick D, Bruckner MK (1995) Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer’s disease. Neuroscience 68:5–18

    Article  PubMed  CAS  Google Scholar 

  62. 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 225:5446–5545

    Google Scholar 

  63. Pérez, MR, Cuadros M, Benítez J, Jiménez J (2004) Interaction of Alzheimer’s disease amyloid α peptide fragment 25–35 with tau protein, and with a tau peptide containing the microtubule binding domain. J Alz Dis 6:461–467

    Google Scholar 

  64. Guo JT, Arai J, Miklossy J, McGeer P (2006) Tau forms soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease. Proc Natl Acad Sci USA 103:1953–1958

    Article  PubMed  CAS  Google Scholar 

  65. Takashima A, Murayama M, Murayama O, Kohno T, Honda T et al (1998) Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci USA 95:9637–9641

    Article  PubMed  CAS  Google Scholar 

  66. Geddes JW (2005) alpha-Synuclein: A potent inducer of tau pathology. Exp Neurol 192:244–225

    Article  PubMed  CAS  Google Scholar 

  67. Giasson BI, Forman M, Higuchi M, Golbe L, Graves C, Kotzbauer P, Trojanowski JQ, Lee VM-Y (2003) Initiation and synergistic fibrillization of tau and alpha synuclein. Science 300:636–640

    Article  PubMed  CAS  Google Scholar 

  68. Greenwood JA, Scott CW, Spreen RC, Caputo CB, Johnson GV (1994) Identification of phosphorylation sites in tau protein, Biochem. J. Johnson, Casein kinase II preferentially phosphorylates human tau. isoforms containing an amino-terminal insert. J Biol Chem 301:871–877

    Google Scholar 

  69. Sacher ME, Athlan S, Mushynski WE (1995) Phosphorylation of Neurofilament Proteins. In: Malhotra SK (ed) Advances in neural science. 47–65

    Google Scholar 

  70. Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G (1998) Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111:3167–3177

    PubMed  CAS  Google Scholar 

  71. Lee G (2005) Tau and src family tyrosine kinases. Biochim Biophys Acta 1739:323–330

    Article  PubMed  CAS  Google Scholar 

  72. Sharma VM, Litersky JM, Bhaskar K, Lee G (2007) Tau impacts on growth-factor-stimulated actin remodeling. J. Cell Sci 120:748–757

    Article  CAS  Google Scholar 

  73. Derkinderen P, Scales TM, Hanger DP, Leung KY, Byers HL, Ward MA, Lenz C, Price C, Bird IN, Perera T, Kellie S, Williamson R, Noble W, Van Etten RA, Leroy K, Brion JP, Reynolds CH, Anderton BH (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25:6584–6593

    Article  PubMed  CAS  Google Scholar 

  74. Lebouvier T, Scales TM, Hanger DP, Geahlen RL, Lardeux B, Reynolds CH, Anderton BH, Derkinderen P (2007) The microtubule-associated protein tau is phosphorylated by Syk. Biochim Biophys Acta 1783:188–192

    Article  PubMed  CAS  Google Scholar 

  75. Lee H et al (2004) The microtubule plus end tracking protein Orbit/MAST/CLASP acts downstream of the tyrosine kinase Abl in mediating axon guidance. Neuron; 42:913–926

    Article  PubMed  CAS  Google Scholar 

  76. Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J (2002) Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau. J Neurosci 22:698–707

    PubMed  CAS  Google Scholar 

  77. Iqbal KC, Alonso A, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198–210

    Article  PubMed  CAS  Google Scholar 

  78. Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C et al (2002) Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J. Neurochem 75:2155–2162

    Article  Google Scholar 

  79. Merrick SE, Demoise DC, Lee VMY (1996) Site-specific dephosphorylation of tau protein at Ser202/Thr205 in response to microtubule depolymerization in cultured human neurons involves protein phosphatase 2A. J Biol Chem 271:5589–5594

    Article  PubMed  CAS  Google Scholar 

  80. Drewes G, Mandelkow EM, Baumann K et al (1993) Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcineurin and phosphatase 2A. FEBS Lett 336:425–432

    Article  PubMed  CAS  Google Scholar 

  81. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B, and PP5 to the regulation of tau phosphorylation. Euro J Neurosci 22:1942–1950

    Article  Google Scholar 

  82. Matsuo EK, Shin R-W, Billingsley ML, Van de Voorde A, O’Connor M, Trojanowski JQ, Lee VM-Y (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s Disease paired helical filament tau. Neuron 13:989–100

    Google Scholar 

  83. Díaz-Hernández M, Gómez-Ramos A, Rubio A, Gómez-Villafuertes R, Naranjo J, Miras-Portugal MS, Avila J (2010) Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285:32539–32548

    Article  PubMed  CAS  Google Scholar 

  84. He HJ, Wang XS, Pan R, Wang DL, Liu MN, He RQ (2009) The proline rich domain of tau plays a role in interactions with actin. BMC Cell Biol 10:81–93

    Article  PubMed  CAS  Google Scholar 

  85. Yu JZ, Rasenick MM (2006) Tau associates with actin in differentiating PC12 cells. FASEB J. 20:1452–1461

    Article  PubMed  CAS  Google Scholar 

  86. Roger B, Al Bassam J, Dehmelt L, Milligan RA, Halpain S (2004) MAP2c, but not tau, binds and bundles F-actin via its microtubule binding domain. Curr Biol 14:363–371

    Article  PubMed  CAS  Google Scholar 

  87. Fischer D, Mukrasch MD, Biernat J, Bibow S, Blackledge M, Griesinger C, Mandelkow E, Zweckstetter M (2009) Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to microtubules. Biochemistry 48:10047–10055

    Article  PubMed  CAS  Google Scholar 

  88. Kim W, Lee S, Hall GF (2010) Secretion of human tau fragments resembling CSF-tau in Alzheimer’s disease is modulated by the presence of the exon 2 insert. FEBS Lett 584:3085–3088

    Article  PubMed  CAS  Google Scholar 

  89. Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL Hyman BT, Feany MB (2007) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9:139–148

    Article  PubMed  CAS  Google Scholar 

  90. Blard O, Feuillette S, Bou J, Chaumette B, Frebourg T, Campion D, Lecourtois M (2007) Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila. Hum Mol Genet 16:555–566

    Article  PubMed  CAS  Google Scholar 

  91. Lee S, Jung C, Lee G, Hall GF (2009) Exonic point mutations of human tau enhance its toxicity and cause characteristic changes in neuronal morphology, tau distribution and tau phosphorylation in the lamprey cellular model of tauopathy. J Alz Dis 16:99–111

    CAS  Google Scholar 

  92. Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271:32789–32795

    Article  PubMed  CAS  Google Scholar 

  93. Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA, Spillantini MG (2007) Interaction of tau protein with the dynactin complex. Embo J 26:4546–4554

    Article  PubMed  CAS  Google Scholar 

  94. Sahara N, Maeda S, Takashima A (2008) Tau Oligomerization: A Role for Tau Aggregation Intermediates Linked to Neurodegeneration. Curr Alz Res 5:591–598

    Article  CAS  Google Scholar 

  95. Mandelkow E, von Bergen M, Biernat J, Mandelkow EM (2007) Structural principles of tau and the paired helical filaments of Alzheimer’s disease. Brain Pathol 17:83–90

    Article  PubMed  CAS  Google Scholar 

  96. Sarkar M, Kuret J, Lee G (2008) Two motifs within the tau microtubule binding domain mediate its association with the hsc70 molecular chaperone. J Neurosci Res 86:2763–2773

    Article  PubMed  CAS  Google Scholar 

  97. Shimura H, Schwartz D, Gygi SP, Kosik KS (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–4876

    Article  PubMed  CAS  Google Scholar 

  98. Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP (1999) The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399:784–788

    Article  PubMed  CAS  Google Scholar 

  99. Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (1999) alpha-Synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481–25489

    Article  PubMed  CAS  Google Scholar 

  100. Cairns N, Lee V M-Y, Trojanowski JQ (2004) The cytoskeleton in neurodegenerative diseases. J Pathol 204:438–449

    Article  PubMed  CAS  Google Scholar 

  101. Benussi L, Ghidoni R, Paterlini A, Nicosia F, Alberici AC, Signorini S, Barbiero L, Binetti G (2005) Interaction between tau and alpha-synuclein proteins is impaired in the presence of P301L tau mutation. Exp Cell Res 308:78–84

    Article  PubMed  CAS  Google Scholar 

  102. Abisambra JF, Blair LJ, Hill SE, Jones JR, Kraft C, Rogers J, Koren J 3rd, Jinwal UK, Lawson L, Johnson AG, Wilcock D, O’Leary JC, Jansen-West K, Muschol M, Golde TE, Weeber EJ, Banko J, Dickey CA (2010) Phosphorylation dynamics regulate hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice. J Neurosci 30:15374–15382

    Article  PubMed  CAS  Google Scholar 

  103. Krylova SM, Musheev M, Nutiu R, Li Y, Lee G, Krylov SN (2005) Tau protein binds single-stranded DNA sequence specifically—the proof obtained in vitro with non-equilibrium capillary electrophoresis of equilibrium mixtures. FEBS Lett 579:1371–1375

    Article  PubMed  CAS  Google Scholar 

  104. Vincent I, Zheng J, Dickson DW, Kress Y, Davies P (1998) Mitotic phosphoepitopes precede paired helical filaments in Alzheimer’s disease. Neurobiol Aging 19:287–296

    Article  PubMed  CAS  Google Scholar 

  105. Vincent I, Jicha G, Rosado M, Dickson DW (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 17:3588–3598

    PubMed  CAS  Google Scholar 

  106. Yang Y, Mufson EJ, Herrup K (2003) Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci 23:2557–2563

    PubMed  CAS  Google Scholar 

  107. Souter S, Lee G (2009) Microtubule-associated protein tau in human prostate cancer cells: Isoforms, phosphorylation, and interactions. J Cell Biochem 108:555–564

    Article  PubMed  CAS  Google Scholar 

  108. Baas PW, Black MM, Banker GA (1989) Changes in dendrite and axon tubule polarity orientation during the development of hippocampal neurons in culture. J Cell Biol 109:3085–3094

    Article  PubMed  CAS  Google Scholar 

  109. Kanai Y, Hirokawa N (1995) Sorting mechanisms of tau and MAP2 in neurons: suppressed axonal transit of MAP2 and locally regulated microtubule binding. Neuron 14:421–432

    Article  PubMed  CAS  Google Scholar 

  110. Mandell J, Banker GA (1996) A spatial gradient of tau protein phosphorylation in nascent axons. J Neurosci 16:5727–5740

    PubMed  CAS  Google Scholar 

  111. Litman P, Barg J, Rindzoonski L, Ginzburg I (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: Implications for neuronal polarity. Neuron 10:627–638

    Article  PubMed  CAS  Google Scholar 

  112. Knops J, Kosik KS, Lee G, Pardee JD, Cohen-Gould L, McConlogue L (1991) Overexpression of tau in a nonneuronal cell induces long cellular processes. J Cell Biol 114:725–733

    Article  PubMed  CAS  Google Scholar 

  113. Tint I, Slaughter T, Fischer I, Black MM (1998) Acute inactivation of tau has no effect o dynamics of microtubules in growing axons of cultured sympathetic neurons. J Neurosci 18:8660–8673

    PubMed  CAS  Google Scholar 

  114. Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369:488–491

    Article  PubMed  CAS  Google Scholar 

  115. Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, Avila J (2002) Participation of structural microtubule-associated proteins (MAPs) in the development of neuronal polarity. J Neurosci Res 67:713–719

    Article  PubMed  CAS  Google Scholar 

  116. Takei Y, Teng J, Harada A, Hirokawa N (2000) Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol 150:989–1000

    Article  PubMed  CAS  Google Scholar 

  117. Kempf M, Clement A, Faissner A, Lee G, Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16:5583–5592

    PubMed  CAS  Google Scholar 

  118. DiTella M, Feiguin F, Morfini G, Caceres A (1994) Microfilament associated growth cone component depends upon tau for its intracellular localization. Cell Motil Cytoskel 29:117–130

    Article  CAS  Google Scholar 

  119. Zmuda J, Rivas R (2000) Actin disruption alters the localization of tau in the growth cones of cerebellar granule neurons. J Cell Sci 113:2797–2809

    PubMed  CAS  Google Scholar 

  120. Goedert M, Jakes R, Crowther RA, Six J, Lubke U, Vandermeeren M, Cras P, Trojanowski JQ, Lee VM-Y (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci USA 90:5066–5070

    Article  PubMed  CAS  Google Scholar 

  121. Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E (2004) MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol 167:99–110

    Article  PubMed  CAS  Google Scholar 

  122. LoPresti P, Szuchet S, Papasozomenos SC, Zinkowski RP, Binder LI (1995) Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc Natl Acad Sci USA 92:10369–10373

    Article  PubMed  CAS  Google Scholar 

  123. Belkadi A, LoPresti P (2008) Truncated Tau with the Fyn-binding domain and without the microtubule-binding domain hinders the myelinating capacity of an oligodendrocyte cell line. J Neurochem 107:351–360

    Article  PubMed  CAS  Google Scholar 

  124. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    Article  PubMed  CAS  Google Scholar 

  125. Schraen-Maschke S, Dhaenens C-M, Delacourte A, Sablonniere B (2004) Microtubule-associated protein tau gene: a risk factor in human neurodegenerative diseases. In: Greenamyre T (ed) Neurobiology of Disease. Elsevier, USA, 15:449–460

    Google Scholar 

  126. Caffrey T, Joachim C, Wade-Martins R (2008) Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT. locus Neurobiol Aging 29:1923–1929

    Article  CAS  Google Scholar 

  127. Spillantini MG, Goedert M (1998) Tau protein pathology in neurodegenerative diseases. Trends Neurosci 10:428–433

    Article  Google Scholar 

  128. Goedert M, Jakes R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739:240–250

    Article  PubMed  CAS  Google Scholar 

  129. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    Article  PubMed  CAS  Google Scholar 

  130. Hasegawa M, Smith MJ, Goedert M (1998) Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 437:207–210

    Article  PubMed  CAS  Google Scholar 

  131. Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Yen SH (1999) Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 447:195–199

    Article  PubMed  CAS  Google Scholar 

  132. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A et al (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914–1917

    Article  PubMed  CAS  Google Scholar 

  133. Yen S, Easson C, Nacharaju P, Hutton M, Yen S-Y (1999) FTDP-17 mutations decrease the susceptibility of tau to calpain 1 digestion. FEBS Lett 461:91–95

    Article  PubMed  CAS  Google Scholar 

  134. Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A (1997) Different distribution of phosphorylated tau protein isoforms in Alzheimer’s and Pick’s diseases. FEBS Lett 412:578–582

    Article  PubMed  CAS  Google Scholar 

  135. Sergeant N, Wattez, A, Delacourte A (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusive “exon 10” isoforms. J Neurochem 72:1243–1249

    Article  PubMed  CAS  Google Scholar 

  136. Buee L, Delacourte A (1999) Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick’s disease. Brain Pathol 9:681–693

    Article  PubMed  CAS  Google Scholar 

  137. Aguzzi A, Sigurdson C, Heikenwaelder M (2008) Molecular mechanisms of prion pathogenesis. Ann Rev Pathol 3:11–40

    Article  CAS  Google Scholar 

  138. Braak H Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropath 82:239–259

    Article  PubMed  CAS  Google Scholar 

  139. Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87:554–567

    Article  PubMed  CAS  Google Scholar 

  140. Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O et al (2008) 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 28:737–748

    Article  PubMed  CAS  Google Scholar 

  141. Jinwal UK, O’Leary JIII, Borysov SI, Jones JR, Li Q, Koren JIII et al (2010) Hsc70 rapidly engages tau after microtubule destabilization. J Biol Chem 285:16798–16805

    Article  PubMed  CAS  Google Scholar 

  142. Yotsumoto K, Saito T, Asada A, Oikawa T, Kimura T, Uchida C, Ishiguro K, Uchida T, Hasegawa M, Hisanaga S (2009) Effect of Pin1 or microtubule binding on dephosphorylation of FTDP-17 mutant Tau. J Biol Chem 284:16840–16847

    Article  PubMed  CAS  Google Scholar 

  143. Alonso AC, Zaidi T, Novak, M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments and straight filaments. Proc Natl Acad Sci USA 98:6923–6928

    Article  PubMed  CAS  Google Scholar 

  144. Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M (2006) Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580:3582–3588

    Article  PubMed  CAS  Google Scholar 

  145. Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, Horowitz PM, Fu Y, Wang T, Cahill ME, Bigio EH, Berry RW, Binder LI (2005) Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging 26:1015–1022

    Article  PubMed  CAS  Google Scholar 

  146. Yin H, Kuret J (2006) C-terminal truncation modulates both nucleation and extension phases of tau fibrillization. FEBS Lett 580:211–215

    Article  PubMed  CAS  Google Scholar 

  147. Bancher C, Brunner C, Lassman H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477:90–99

    Article  PubMed  CAS  Google Scholar 

  148. Litersky JM, Johnson GV (1992) Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J Biol Chem 267:1563–1568

    PubMed  CAS  Google Scholar 

  149. Perry G, Friedman R, Shaw G, Chau V (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci USA 84:3033–3036

    Article  PubMed  CAS  Google Scholar 

  150. Ihara Y (1993) Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron 10:1151–1160

    Article  PubMed  Google Scholar 

  151. Dudek SM, Johnson GV (1993) Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau. J Neurochem 61:1159–1162

    Article  PubMed  CAS  Google Scholar 

  152. Johnson GV, Cox TM, Lockhart JP, Zinnerman MD, Miller ML, Powers R (1997) Transglutaminase activity is increased in Alzheimer’s disease brain. Brain Res 751:323–329

    Article  PubMed  CAS  Google Scholar 

  153. Reynolds MR, Reyes JF, Fu Y, Bigio EH, Guillozet-Bongaarts AL, Berry RW et al (2006) Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer’s disease and other tauopathies. J Neurosci 26:10636–10645

    Article  PubMed  CAS  Google Scholar 

  154. Ledesma MD, Bonay P, Colaco C, Avila J (1994) Analysis of microtubule associated protein tau glycation in paired helical filaments. J Biol Chem 269:21614–21619

    PubMed  CAS  Google Scholar 

  155. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS et al (1994) Glycated tau protein in Alzheimer’s disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91:7787–7791

    Article  PubMed  CAS  Google Scholar 

  156. Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Merkle RK, Gong CX (2002) Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett 512:101–106

    Article  PubMed  CAS  Google Scholar 

  157. Dickey CA, Yue M, Lin WL, Dickson DW, Dunmore JH, Lee WC, Zehr C et al (2006) Deletion of the ubiquitin ligase CHIP leads to the accumulation, but not the aggregation, of both endogenous phospho- and caspase-3-cleaved tau species. J Neurosci 26:6985–6996

    Article  PubMed  CAS  Google Scholar 

  158. Oddo, S (2008) The ubiquitin-proteasome system in Alzheimer’s disease. J Cell Mol Med 12:363–373

    Article  PubMed  CAS  Google Scholar 

  159. Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB et al (2007) The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117:648–658

    Article  PubMed  CAS  Google Scholar 

  160. Keck S, Nitsch R, Grune T, Ullrich O (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 85:115–122

    Article  PubMed  CAS  Google Scholar 

  161. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Ab immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332

    Article  PubMed  CAS  Google Scholar 

  162. Cataldo AM, Barnett JL, Berman SA, Li J, Quarless S, Bursztajn S, Lippa C, Nixon RA (1995) Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron 14:671–680

    Article  PubMed  CAS  Google Scholar 

  163. Williams AL, Jahreiss S, Sarkar S, Saiki FM, Menzies B, Ravikumar B, Rubinsztein DC (2006) Aggregate-prone proteinsare cleared from the cytosol by autophagy: therapeutic implications. Curr Top Dev Biol 76:89–101

    Article  PubMed  CAS  Google Scholar 

  164. Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, Isidoro C, Deture M, Ko LW (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci 27:1119–1130

    Article  PubMed  Google Scholar 

  165. Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11:1107–1117

    Article  PubMed  CAS  Google Scholar 

  166. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122

    PubMed  Google Scholar 

  167. Boland BA, Kumar A, Lee F-M, Platt J, Wegiel J, Yu WH, Nixon, RA (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 28:6926–6937

    Article  PubMed  CAS  Google Scholar 

  168. Nemes Z, Devreese B, Steinert PM, Van Beeumen J, Fesus L (2004) Cross-linking of ubiquitin, HSP27, parkin, and alpha-synuclein by gamma-glutamyl-epsilon-lysine bonds in Alzheimer’s neurofibrillary tangles. FASEB J. 18:1135–1137

    PubMed  CAS  Google Scholar 

  169. Björkdahl C, Sjögren MJ, Zhou X, Concha H, Avila J, Winblad B, Pei JJ (2008) Small heat shock proteins Hsp27 or alphaB-crystallin and the protein components of neurofibrillary tangles: tau and neurofilaments. J Neurosci Res 86:1343–1352

    Article  PubMed  CAS  Google Scholar 

  170. Trojanowski JQ, Lee VM-Y (2005) Pathological tau: a loss of normal function or a gain in toxicity? Nat Neurosci 23:1136–1137

    Article  CAS  Google Scholar 

  171. Feinstein S, Wilson L (2005) Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death. Biochim Biophys Acta 1739:268–279

    Article  PubMed  CAS  Google Scholar 

  172. McKee AC, Kowall NW, Kosik KS (1989) Microtubular reorganization and dendritic growth response in Alzheimer’s disease. Ann Neurol 26:652–659

    Article  PubMed  CAS  Google Scholar 

  173. Alonso, AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule associated proteins 1 and 2 and the disassembly of microtubules. Proc Nat Acad Sci USA 94:298–303

    Article  PubMed  CAS  Google Scholar 

  174. Galloway PG, Perry G, Kosik KS, Gambetti P (1987) Hirano bodies contain tau protein. Brain Res 403:337–340

    Article  PubMed  CAS  Google Scholar 

  175. Kampers T, Friedhoff P, Biernat J, Mandelkow EM (1997) RNA stimulates aggregation of microtubule-associated protein-tau into Alzheimer-like paired helical filaments. FEBS Lett 399:344–349

    Article  Google Scholar 

  176. Goedert M, Jakes R, Spillantini MG, Hasegawa M, Smith MJ, Crowther RA (1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383:550–553

    Article  PubMed  CAS  Google Scholar 

  177. Ginsberg SD, Crino PB, Lee VM-Y, Eberwine JH, Trojanowski JQ (1997) Sequestration of RNA in Alzheimer’s disease neurofibrillary tangles and senile plaques. Ann Neurol 41:200–209

    Article  PubMed  CAS  Google Scholar 

  178. Perez M, Valpuesta JM, Medina M, Montejo de Garcini E, Avila J (1996) Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J Neurochem 67:1183–1190

    Article  PubMed  CAS  Google Scholar 

  179. Goedert M, Jakes R, Crowther RA (1999) Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett 450:306–311

    Article  PubMed  CAS  Google Scholar 

  180. Arriagada PA, Growdon JH, Hedley-White ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s Disease. Neurology 42:631–639

    Article  PubMed  CAS  Google Scholar 

  181. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM (2006) Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 281:1205–1214

    Article  PubMed  CAS  Google Scholar 

  182. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M et al (2005) Tau suppression in a neurodegenerative mouse memory function. Science 309:476–481

    Article  PubMed  CAS  Google Scholar 

  183. Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662

    Article  PubMed  CAS  Google Scholar 

  184. Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168:1598–1607

    Article  PubMed  CAS  Google Scholar 

  185. Makrides V, Shen TE, Bhatia R, Smith BL, Thimm J, Lal R, Feinstein SC (2003) Microtubule-dependent oligomerization of tau. Implications for physiological tau function and tauopathies. J Biol Chem 278:33298–33304

    Article  PubMed  CAS  Google Scholar 

  186. Bretteville A, Planel E (2008) Tau Aggregates: Toxic, Inert, or Protective Species? J Alz Dis 14: 431–436

    Google Scholar 

  187. Maeda S, Sahara N, Saito Y, Murayama S, Ikai A, Takashima A (2006) Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer’s disease. Neurosci Res 54:197–201

    Article  PubMed  CAS  Google Scholar 

  188. Chirita CN, Necula M, Kuret J (2003) Anionic micelles and vesicles induce tau fibrillization in vitro. J Biol Chem 278:25644–25650

    Article  PubMed  CAS  Google Scholar 

  189. Gray EG, Paula-Barbosa M, Roher A (1987) Alzheimer’s disease: paired helical filaments and cytomembranes. Neuropathol Appl Neurobiol 13:91–110

    Article  PubMed  CAS  Google Scholar 

  190. Ho GJ, Hashimoto M, Adame A, Izu M, Alford MF, Thal LJ, Hansen LA, Masliah E (2005) Altered p59Fyn kinase expression accompanies disease progression in Alzheimer’s disease: implications for its functional role. Neurobiol Aging 26:625–635

    Article  PubMed  CAS  Google Scholar 

  191. Bhaskar K, Hobbs GA, Yen S-H, Lee G (2010) Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy. Neuropathol Appl Neurobiol 36:462–477

    Article  PubMed  CAS  Google Scholar 

  192. Farah CA, Perreault S, Liazoghli D, Desjardins M, Anton A, Lauzon M, Paiement J, Leclerc N (2006) Tau interacts with Golgi membranes and mediates their association with microtubules. Cell Motil Cytoskeleton 63:710–724

    Article  PubMed  CAS  Google Scholar 

  193. Kim W, Lee S, Jung C, Ahmed A, Lee G, Hall GF (2010) Interneuronal transfer of human tau between Lamprey central neurons in situ. J Alz Dis 19:647–664

    CAS  Google Scholar 

  194. Hall GF, Chu B, Lee G, Yao J (2000) Human tau filaments induce microtubule and synapse loss in vertebrate central neurons. J Cell Sci 113:1373–1387

    PubMed  CAS  Google Scholar 

  195. Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E (2006) Global hairpin folding of tau in solution. Biochemistry 45:2283–2293

    Article  PubMed  CAS  Google Scholar 

  196. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, Bennett DA, Cryns VL, Berry RW, Binder LI (2004) Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci 24:7895–7902

    Article  PubMed  CAS  Google Scholar 

  197. Horowitz PM, LaPointe N, Guillozet-Bongaarts AL, Berry RW, Binder LI (2006) N-terminal fragments of tau inhibit full-length tau polymerization in vitro. Biochemistry 45:12859–12866

    Article  PubMed  CAS  Google Scholar 

  198. Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995) Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–888

    Article  PubMed  CAS  Google Scholar 

  199. Bloom GS, Ren K, Glabe C (2005) Cultured cell and transgenic mouse models for tau pathology linked to b-amyloid. Biochim Biophys Acta 1739:116–124

    Article  PubMed  CAS  Google Scholar 

  200. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci USA 99:6364–6369

    Article  PubMed  CAS  Google Scholar 

  201. King ME, Kan H, Baas PW, Erisir A, Glabe C, Bloom GS (2006) Tau-dependent microtubule disassembly initiated by prefibrillar beta-amyloid. J Cell Biol 175:541–546

    Article  PubMed  CAS  Google Scholar 

  202. Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 1–42 fibrils. Science 293:1491–1495

    Article  PubMed  CAS  Google Scholar 

  203. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754

    Article  PubMed  CAS  Google Scholar 

  204. Park SY, Ferreira A (2005) The generation of a 17kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J Neurosci 25:5365–5375

    Article  PubMed  CAS  Google Scholar 

  205. Amadoro G, Serafino AL, Barbato C, Ciotti MT, Sacco A, Calissano P, Canu N (2004) Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons. Cell Death Differ 11:217–230

    Article  PubMed  CAS  Google Scholar 

  206. Corsetti V, Amadoro G, Gentile A, Capsoni S, Ciotti MT, Cencioni MT, Atlante A, Canu N, Rohn TT, Cattaneo A et al (2008) Identification of a caspase-derived N-terminal tau fragment in cellular and animal Alzheimer’s disease models. Mol Cell Neurosci 38:381–392

    Article  PubMed  CAS  Google Scholar 

  207. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156:1051–1063

    Article  PubMed  CAS  Google Scholar 

  208. Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E (2004) MARK/PAR-1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol 167:99–110

    Article  PubMed  CAS  Google Scholar 

  209. Leroy K, Bretteville A, Schindowski K, Gilissen E, Authelet M, De Decker R, Yilmaz Z, Buee L, Brion JP (2007) Early axonopathy preceding neurofibrillary tangles in mutant tau transgenic mice. Am J Pathol 171:976–992

    Article  PubMed  CAS  Google Scholar 

  210. Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA (2008) Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci 28:1682–1687

    Article  PubMed  CAS  Google Scholar 

  211. Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089

    Article  PubMed  CAS  Google Scholar 

  212. Stoothoff W, Jones PB, Spires-Jones TL, Joyner D, Chhabra E, Bercury K et al (2009) Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J Neurochem 111:417–427

    Article  PubMed  CAS  Google Scholar 

  213. LaPointe NE, Morfini G, Pigino G, Gaisina IN, Kozikowski AP, Binder LI, Brady ST (2009) The amino terminus of tau inhibits kinesin dependent axonal transport: implications for filament toxicity. J Neurosci Res 87:440–451

    Article  PubMed  CAS  Google Scholar 

  214. Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA et al (2009) Axonal transport defects in neurodegenerative diseases. J Neurosci 29:12776–12786

    Article  PubMed  CAS  Google Scholar 

  215. Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288

    Article  PubMed  CAS  Google Scholar 

  216. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K et al (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87:1561–1565

    Article  PubMed  CAS  Google Scholar 

  217. Zhu X, Moreira PI, Smith MA, Perry G (2005) Alzheimer’s disease: an intracellular movement disorder? Trends Mol Med 11:391–393

    Article  PubMed  CAS  Google Scholar 

  218. Her L, Goldstein L (2008) Enhanced sensitivity of striatal neurons to axonal transport defects induced by mutant huntingtin. J Neurosci 28:13662–13672

    Article  PubMed  CAS  Google Scholar 

  219. Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol 57:451–484

    Article  PubMed  CAS  Google Scholar 

  220. Schindowski K, Belarbi K, Buee L (2008) Neurotrophic factors in Alzheimer’s disease: role of axonal transport. Genes Brain Behav 7(Suppl. 1):43–56

    PubMed  CAS  Google Scholar 

  221. Kowall NW, Kosik KS (1987) Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer’s disease. Ann Neurol 22:639–643

    Article  PubMed  CAS  Google Scholar 

  222. Braak H Braak E (1988) Neuropil threads occur in dendrites of tangle-bearing nerve cells. Neuropathol Appl Neurobiol 14:39–44

    Article  PubMed  CAS  Google Scholar 

  223. Ihara Y (1988) Massive somatodendritic sprouting of cortical neurons in Alzheimer’s Disease. Brain Res 459:138–144

    Article  PubMed  CAS  Google Scholar 

  224. 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

    Article  PubMed  CAS  Google Scholar 

  225. Perry G, Kawai M, Tabaton M, Onorato M, Mulvihill P, Richey P, Morandi A, Connolly JA, Gambetti P (1991) Neuropil threads of Alzheimer’s disease show a marked alteration of the normal cytoskeleton. J Neurosci 11:1748–1755

    PubMed  CAS  Google Scholar 

  226. Hall GF, Poulos A, Cohen MJ (1989) Sprouts emerging from the dendrites of axotomized lamprey central neurons have axonlike ultrastructure. J Neurosci 9:588–599

    PubMed  CAS  Google Scholar 

  227. Hall GF, Yao J, Selzer M, Kosik KS (1997) Cytoskeletal correlates to cell polarity loss following axotomy of lamprey central neurons. J Neurocytol 26:733–753

    Article  PubMed  CAS  Google Scholar 

  228. Linda H, Risling M, Cullheim S (1985) ‘Dendraxons’ in regenerating motoneurons in the cat: do dendrites generate new axons after central axotomy? Brain Res 358:329–333

    Article  PubMed  CAS  Google Scholar 

  229. Cho EY, So KF (1992) Characterization of the sprouting response of axon-like processes from retinal ganglion cells after axotomy in adult hamsters: a model using intravitreal implantation of a peripheral nerve. J Neurocytol 21:589–603

    Article  PubMed  CAS  Google Scholar 

  230. Rose PK, MacDermid V, Joshi M, Neuber-Hess M (2001) Emergence of axons from distal dendrites of adult mammalian neurons following a permanent axotomy. Eur J Neurosci 13:1166–1176

    Article  PubMed  CAS  Google Scholar 

  231. Hall GF (1993) Cellular responses of identified lamprey central neurons to axonal and dendritic injury. Ann NY Acad Sci 679:43–64

    Article  PubMed  CAS  Google Scholar 

  232. Hall GF (1999) Neuronal morphology: development and maintenance of neuronal polarity. In: Adelman and Smith (ed) Encyclopedia of neuroscience. Elsevier, New York, 1409–1413

    Google Scholar 

  233. Arimura N, Kaibuchi K (2007) Neuronal polarity: From extracellular signals to intracellular mechanisms. Nat Rev Neurosci 8:194–205

    Article  PubMed  CAS  Google Scholar 

  234. Fenrich KK, Skelton N, MacDermid VE, Meehan CF, Armstrong S et al (2007) Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy. J Comp Neurol 502:1079–1097

    Article  PubMed  CAS  Google Scholar 

  235. Stone MC, Nguyen MM, Tao J, Allender DL, Rolls MM (2010) global up-regulation of microtubule dynamics and polarity reversal during regeneration of an axon from a dendrite. Mol Biol Cell 21:767–777

    Article  PubMed  CAS  Google Scholar 

  236. Matenia D, Mandelkow EM (2009) The tau of MARK: a polarized view of the cytoskeleton. TIBS 34:7

    Google Scholar 

  237. Kim WY, Zhou FQ, Zhou J, Yokota Y, Wang YM, Yoshimura T, Kaibuchi K, Woodgett JR, Anton ES, Snider WD (2006) Essential roles for GSK-3s and GSK-3 primed substrates in neurotrophin-induced and hippocampal axon growth. Neuron 52:981–996

    Article  PubMed  CAS  Google Scholar 

  238. Soutar MP, Thornhill P, Cole AR, Sutherland C (2009) Increased CRMP2 phosphorylation is observed in Alzheimer’s disease; does this tell us anything about disease development? Curr Alz Res 6:269–278

    Article  CAS  Google Scholar 

  239. Terabayashi T, Itoh TJ, Yamaguchi H, Yoshimura Y, Funato Y et al (2007) Polarity-regulating kinase partitioning-defective 1/microtubule affinity-regulating kinase 2 negatively regulates development of dendrites on hippocampal neurons. J Neurosci 27:13098–13107

    Article  PubMed  CAS  Google Scholar 

  240. Cole AR, Soutar MP, Rembutsu M, van Aalten L, Hastie CJ, McLauchlan H, Peggie M, Balastik M, Lu KP, Sutherland C (2008) Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J Biol Chem 283:18227–18237

    Article  PubMed  CAS  Google Scholar 

  241. Thies E, Mandelkow EM (2007) Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci 27:2896–2907

    Article  PubMed  CAS  Google Scholar 

  242. Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J (2001) Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem 276:38193–38200

    PubMed  CAS  Google Scholar 

  243. Morita T, Sobue K (2009) Specification of neuronal polarity regulated by local translation of CRMP2 and tau via the mTOR-p70S6K pathway. JBC 284:27734–27745

    Article  CAS  Google Scholar 

  244. Nayeem N, Kerr F, Naumann H, Linehan J, Lovestone S, Brandner S (2007) Hyperphosphorylation of tau and neurofilaments and activation of CDK5 and ERK1/2 in PTEN-deficient cerebella. Mol Cell Neurosci 34:400–408

    Article  PubMed  CAS  Google Scholar 

  245. de la Monte SM, Ng S-C, Hsu DW (1995) Aberrant GAP-43 gene expression in Alzheimer’s disease. Am J Pathol 147:934–946

    PubMed  Google Scholar 

  246. Yoshida H, Watanabe A, Ihara Y (1998) Collapsin response mediator protein-2 is associated with neurofibrillary tangles in Alzheimer’s disease. J Biol Chem 273:9761–9768

    Article  PubMed  CAS  Google Scholar 

  247. Götz J, Probst A, Spillatini MG, Schäfer T, Jakes R, Bürki K, Goedert M (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14:1304–1313

    PubMed  Google Scholar 

  248. Brion JP, Tremp G, Octave JN (1999) Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer’s disease. Am J Pathol 54:255–270

    Article  Google Scholar 

  249. Hall GF, Yao J, Lee G (1997) Tau overexpressed in identified lamprey neurons in situ is spatially segregated by phosphorylation state, forms hyperphosphorylated, dense aggregations and induces neurodegeneration. Proc Nat Acad Sci USA 94:4733–4738

    Article  PubMed  CAS  Google Scholar 

  250. Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, Trojanowski JQ, Lee VM (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24:751–762

    Article  PubMed  CAS  Google Scholar 

  251. Spittaels K, Van Den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, Geerts H, Mercken M, Sciot R et al (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 155:2153–2165

    Article  PubMed  CAS  Google Scholar 

  252. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

    Google Scholar 

  253. Uryu K, Chen XH, Martinez D et al (2007) Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 208:185–192

    Article  PubMed  CAS  Google Scholar 

  254. Singleton RH, Zhu J, Stone JR, Povlishock JT (2002) Traumatically induced axotomy adjacent to the soma does not result in acute neuronal death. J Neurosci 22:791–802

    PubMed  CAS  Google Scholar 

  255. McKee A, Cantu R, Nowinski C et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735

    Article  PubMed  Google Scholar 

  256. Lafont F, Rouget M, Triller A, Prochiantz A, Rousselet A (1992) In vitro control of neuronal polarity by glycosaminoglycans. Development 114:17–29

    PubMed  CAS  Google Scholar 

  257. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, Wölfing H, Chieng BC, Christie MJ, Napier IA, Eckert A, Staufenbiel M et al (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142:387–397

    Article  PubMed  CAS  Google Scholar 

  258. Su JH, Deng G, Cotman CW (1997) Transneuronal degeneration in the spread of Alzheimer’s disease pathology: immunohistochemical evidence for the transmission of tau hyperphosphorylation. Neurobiol Dis 4:365–375

    Article  PubMed  CAS  Google Scholar 

  259. Armstrong RA, Cairns NJ, Lantos PL (2001) What does the study of spatial patterns tell us about the pathogenesis of neurodegenerative disorders? Neuropathology 21:1–12

    Article  PubMed  CAS  Google Scholar 

  260. Götz J, Schonrock N, Vissel B, Ittner LM (2009) Alzheimer’s disease selective vulnerability and modeling in transgenic mice. J Alz Dis 18:243–251

    Google Scholar 

  261. Miller G (2009) Could they all be prion diseases? Science 326:1327–1329

    Google Scholar 

  262. Sydow A, Mandelkow EM (2010) ‘Prion-like’ propagation of mouse and human tau aggregates in an inducible mouse model of tauopathy. Neurodegenerative Dis 7:28–31

    Article  CAS  Google Scholar 

  263. Nickel W (2005) Unconventional secretory routes: direct protein export across the plasma membrane of mammalian cells. Traffic 6:607–614

    Article  PubMed  CAS  Google Scholar 

  264. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851

    Article  PubMed  CAS  Google Scholar 

  265. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G(2004) Cells release prions in association with exosomes. Proc Natl Acad Sci USA 101:9683–9688

    Article  PubMed  CAS  Google Scholar 

  266. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci USA 103:11172–11177

    Article  PubMed  CAS  Google Scholar 

  267. Hall GF, Lee S, Yao, J (2002) Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by application of a compound which inhibits tau filament formation in vitro. J. Mol. Neurosci 19:253–260

    CAS  Google Scholar 

  268. Gomez-Ramos A, Diaz-Hernandez M, Cuadros R, Hernandez F, Avila, J (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580:4842–4850

    Article  PubMed  CAS  Google Scholar 

  269. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    Article  PubMed  CAS  Google Scholar 

  270. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913

    Article  PubMed  CAS  Google Scholar 

  271. Johnson G, Seubert P, Cox TM, Motter R, Brown JP, Galasko D (1997) The tau protein in human cerebrospinal fluid in Alzheimer’s disease consists of proteolytically derived fragments. J Neurochem 68:430–433

    Article  PubMed  CAS  Google Scholar 

  272. Urakami K, Wada K, Arai H, Sasaki H, Kanai M, Shoji M, Ishizu H, Kashihara K, Yamamoto M, Tsuchiya-Ikemoto K, Morimatsu M, Takashima H, Nakagawa M, Kurokawa K, Maruyama H, Kaseda Y, Nakamura S, Hasegawa K, Oono H, Hikasa C, Ikeda K, Yamagata K, Wakutani Y, Takeshima T, Nakashima K (2001) Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J Neurol Sci 183:95–98

    Article  PubMed  CAS  Google Scholar 

  273. Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Kosaka K, Arai H (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294

    Article  PubMed  CAS  Google Scholar 

  274. Giaccone G, Mangieri M, Capobianco R, Limido L, Hauw JJ, Haïk S, Fociani P, Bugiani O, Tagliavini F (2008) Tauopathy in human and experimental variant Creutzfeldt-Jakob disease. Neurobiol Aging 29:1864–1873

    Article  PubMed  CAS  Google Scholar 

  275. Fein JA, Sokolow S, Miller CA, Vinters HV, Yang F, Cole GM, Gylys KH (2008) Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am J Pathol 172:1683–1692

    Article  PubMed  CAS  Google Scholar 

  276. Zhao Z, Ksiezak-Reding H, Wang J, Pasinetti GM (2005) Expression of tau reduces secretion of Abeta without altering the amyloid precursor protein content in CHOsw cells. FEBS Lett 579:2119–2124

    Article  PubMed  CAS  Google Scholar 

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  1. Center for Cellular Neuroscience and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, 198 Riverside St. Lowell, 01854, Lowell, MA, USA

    Garth F. Hall

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  1. Australia for Medical Research, Iron Metabolism Program, Children's Cancer Institute, Randwick, New South Wales, Australia

    Maria Kavallaris

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Hall, G.F. (2012). The Biology and Pathobiology of Tau Protein. In: Kavallaris, M. (eds) Cytoskeleton and Human Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-788-0_15

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