Tau in physiology and pathology

Key Points

  • Tauopathies are classified into several groups based on the isoform composition of tau aggregates. The splicing of the gene encoding tau is regulated by multiple factors besides tau mutations.

  • Tau is a natively unfolded protein that shows no tendency for aggregation by itself. Post-translational modifications may modify the processes of tau oligomerization, aggregation and tau-induced neurodegeneration.

  • The polarized distribution of tau into the axonal compartment of neurons is determined by multiple mechanisms. In addition, part of tau is actively released into extracellular space.

  • Besides stabilizing microtubules, regulating their dynamic instability and supporting axonal transport, tau can interact with various cell components and thus serves other functions in various other processes, including neuronal activity, neurogenesis, iron export and long-term depression.

  • Pathological tau may induce neurotoxicity owing to its loss of function, toxic gain of function or its mislocalization, which mediates amyloid-β-induced toxicity.

  • Several tau- or microtubule-based therapeutic approaches have been proposed, including tau aggregation inhibitors, inhibitors of kinases targeting tau, inhibition of tau acetylation, stabilization of microtubules, reduction of tau by antisense oligonucleotides, and immunotherapy using antibodies against tau or phosphorylated tau.


Tau is a microtubule-associated protein that has a role in stabilizing neuronal microtubules and thus in promoting axonal outgrowth. Structurally, tau is a natively unfolded protein, is highly soluble and shows little tendency for aggregation. However, tau aggregation is characteristic of several neurodegenerative diseases known as tauopathies. The mechanisms underlying tau pathology and tau-mediated neurodegeneration are debated, but considerable progress has been made in the field of tau research in recent years, including the identification of new physiological roles for tau in the brain. Here, we review the expression, post-translational modifications and functions of tau in physiology and in pathophysiology.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The human MAPT gene and the splice isoforms of tau in the human brain.
Figure 2: Tau structure, domains, mutations and pathological phosphorylation sites.
Figure 3: Functions of tau.


  1. 1

    Weingarten, M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl Acad. Sci. USA 72, 1858–1862 (1975). This study led to the discovery of tau protein as a microtubule-associated protein.

  2. 2

    Kidd, M. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature 197, 192–193 (1963). First observation and naming of 'paired helical filaments' in the brains of patients with AD.

  3. 3

    Alzheimer, A. Über eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatrie Psychisch-gerichtl. Med. 64, 146–148 (in German) (1907). Original description of the pathology of 'Alzheimer disease'.

  4. 4

    Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).

  5. 5

    Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998). This study identifies MAPT mutations in the human brain and demonstrates that tau pathology is sufficient to cause neurodegeneration.

  6. 6

    Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754 (2007). This study demonstrates in a mouse model that tau is necessary for Aβ-induced excitotoxicity.

  7. 7

    Holmes, B. B. & Diamond, M. I. Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target. J. Biol. Chem. 289, 19855–19861 (2014).

  8. 8

    Yoshiyama, Y., Lee, V. M. & Trojanowski, J. Q. Therapeutic strategies for tau mediated neurodegeneration. J. Neurol. Neurosurg. Psychiatry 84, 784–795 (2013).

  9. 9

    Brettschneider, J., Del Tredici, K., Lee, V. M. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat. Rev. Neurosci. 16, 109–120 (2015).

  10. 10

    Andreadis, A. Misregulation of tau alternative splicing in neurodegeneration and dementia. Prog. Mol. Subcell. Biol. 44, 89–107 (2006).

  11. 11

    LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P. & Binder, L. I. Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc. Natl Acad. Sci. USA 92, 10369–10373 (1995).

  12. 12

    Lee, G., Cowan, N. & Kirschner, M. The primary structure and heterogeneity of tau protein from mouse brain. Science 239, 285–288 (1988). This was the first study to sequence tau protein, highlighting its hydrophilic nature and the presence of pseudorepeats.

  13. 13

    Dickson, D. W., Kouri, N., Murray, M. E. & Josephs, K. A. Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J. Mol. Neurosci. 45, 384–389 (2011).

  14. 14

    Orozco, D. et al. Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. EMBO Rep. 13, 759–764 (2012).

  15. 15

    Smith, P. Y. et al. MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy. Hum. Mol. Genet. 20, 4016–4024 (2011).

  16. 16

    Santa-Maria, I. et al. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J. Clin. Invest. 125, 681–686 (2015).

  17. 17

    Moschner, K. et al. RNA protein granules modulate tau isoform expression and induce neuronal sprouting. J. Biol. Chem. 289, 16814–16825 (2014).

  18. 18

    Bruch, J., Xu, H., De Andrade, A. & Hoglinger, G. Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation. PLoS ONE 9, e113070 (2014).

  19. 19

    Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E. M. & Mandelkow, E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349 (1996).

  20. 20

    Violet, M. et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front. Cell Neurosci. 8, 84 (2014).

  21. 21

    Goedert, M. & Jakes, R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 9, 4225–4230 (1990).

  22. 22

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

  23. 23

    Frappier, T. F., Georgieff, I. S., Brown, K. & Shelanski, M. L. τ regulation of microtubule-microtubule spacing and bundling. J. Neurochem. 63, 2288–2294 (1994).

  24. 24

    Liu, C. & Gotz, J. Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS ONE 8, e84849 (2013).

  25. 25

    Zhong, Q., Congdon, E. E., Nagaraja, H. N. & Kuret, J. Tau isoform composition influences rate and extent of filament formation. J. Biol. Chem. 287, 20711–20719 (2012).

  26. 26

    Kosik, K. S., Orecchio, L. D., Bakalis, S. & Neve, R. L. Developmentally regulated expression of specific tau sequences. Neuron 2, 1389–1397 (1989).

  27. 27

    Takuma, H., Arawaka, S. & Mori, H. Isoforms changes of tau protein during development in various species. Brain Res. Dev. Brain Res. 142, 121–127 (2003).

  28. 28

    Llorens-Martin, M. et al. Tau isoform with three microtubule binding domains is a marker of new axons generated from the subgranular zone in the hippocampal dentate gyrus: implications for Alzheimer's disease. J. Alzheimers Dis. 29, 921–930 (2012).

  29. 29

    Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E. & Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl Acad. Sci. USA 85, 4051–4055 (1988). This paper reveals the sequence of human tau protein and its presence in the core of tau filaments.

  30. 30

    Adams, S. J. et al. Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration. Am. J. Pathol. 175, 1598–1609 (2009).

  31. 31

    Lee, G., Newman, S. T., Gard, D. L., Band, H. & Panchamoorthy, G. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 111, 3167–3177 (1998).

  32. 32

    Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010). This paper shows that dendritic tau plays a part in mediating Aβ-induced hyperexcitotoxicity, by regulating the synaptic distribution of FYN.

  33. 33

    Brion, J. P., Passareiro, H., Nunez, J. & Flament-Durand, J. Mise en evidence immunologique de la proteine tau au nivea u des lesions de degenerescence neurofibrillaire de la maladie d'Alzheimer. Arch. Biol. (Bruxelles) 95, 229–235 (in French) (1985). This study provided the first evidence that NFTs in the AD brain contain tau protein.

  34. 34

    Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986). This study demonstrates that tau protein is present in AD NFTs in a hyperphosphorylated state.

  35. 35

    Mukrasch, M. D. et al. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 7, e34 (2009). A study of full-length tau by solution nuclear magnetic resonance, demonstrating that the majority of the polypeptide chain is in a flexible random-coil conformation, with very few transient secondary-structure elements.

  36. 36

    Kadavath, H. et al. Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc. Natl Acad. Sci. USA 112, 7501–7506 (2015). This paper found that tau binds at the interface between α-tubulin–β-tubulin heterodimers through residues including the motifs that are essential for the pathological aggregation of tau, suggesting that there is competition between physiological interaction and pathogenic misfolding.

  37. 37

    Gruning, C. S. et al. Alternative conformations of the Tau repeat domain in complex with an engineered binding protein. J. Biol. Chem. 289, 23209–23218 (2014).

  38. 38

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

  39. 39

    Wischik, C. M. et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4506–4510 (1988).

  40. 40

    Wegmann, S., Medalsy, I. D., Mandelkow, E. & Muller, D. J. The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush. Proc. Natl Acad. Sci. USA 110, E313–E321 (2013).

  41. 41

    Kanemaru, K., Takio, K., Miura, R., Titani, K. & Ihara, Y. Fetal-type phosphorylation of the tau in paired helical filaments. J. Neurochem. 58, 1667–1675 (1992).

  42. 42

    Köpke, E. et al. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268, 24374–24384 (1993).

  43. 43

    Matsuo, E. S. et al. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron 13, 989–1002 (1994). This paper reveals that the post-mortem delay can cause the dephosphorylation of tau by phosphatases, leading to underestimation of the phosphorylation level of tau in vivo , and shows that tau is physiologically phosphorylated at many of the same sites that are phosphorylated in PHF-tau.

  44. 44

    Morris, M. et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 18, 1183–1189 (2015).

  45. 45

    Hanger, D. P., Anderton, B. H. & Noble, W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol. Med. 15, 112–119 (2009).

  46. 46

    Rosseels, J. et al. Tau monoclonal antibody generation based on humanized yeast models: impact on Tau oligomerization and diagnostics. J. Biol. Chem. 290, 4059–4074 (2015).

  47. 47

    Vega, I. E. et al. Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res. Mol. Brain Res. 138, 135–144 (2005).

  48. 48

    Gong, C. X., Singh, T. J., Grundke-Iqbal, I. & Iqbal, K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61, 921–927 (1993).

  49. 49

    Chen, S., Li, B., Grundke-Iqbal, I. & Iqbal, K. IPP2A1 affects tau phosphorylation via association with the catalytic subunit of protein phosphatase 2A. J. Biol. Chem. 283, 10513–10521 (2008).

  50. 50

    Sontag, E. et al. Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J. Neuropathol. Exp. Neurol. 63, 1080–1091 (2004).

  51. 51

    Planel, E. et al. 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 (2004).

  52. 52

    Arendt, T. et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J. Neurosci. 23, 6972–6981 (2003). The authors found that tau hyperphosphorylation occurs physiologically and reversibly in hibernating animals without forming tau aggregates.

  53. 53

    Planel, E. et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J. Neurosci. 27, 3090–3097 (2007). This paper shows that anaesthesia can cause tau hyperphosphorylation owing to inhibition of phosphatase activity by hypothermia.

  54. 54

    Lu, P. J., Wulf, G., Zhou, X. Z., Davies, P. & Lu, K. P. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784–788 (1999).

  55. 55

    Kondo, A. et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436 (2015).

  56. 56

    Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010). This study shows that the hyperphosphorylation of tau drives its entry into postsynaptic terminals, resulting in synaptic dysfunction.

  57. 57

    Thies, E. & Mandelkow, E. M. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J. Neurosci. 27, 2896–2907 (2007). This study demonstrates that missorting of phosphorylated tau into dendrites and spines leads to transport inhibition and loss of spines.

  58. 58

    Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E. M. Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).

  59. 59

    Guillozet-Bongaarts, A. L. et al. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J. Neurochem. 97, 1005–1014 (2006).

  60. 60

    Dickey, C. A. et al. The high-affinity HSP90–CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117, 648–658 (2007).

  61. 61

    Ittner, L. M., Ke, Y. D. & Gotz, J. Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J. Biol. Chem. 284, 20909–20916 (2009).

  62. 62

    Bhaskar, K., Yen, S. H. & Lee, G. Disease-related modifications in tau affect the interaction between Fyn and Tau. J. Biol. Chem. 280, 35119–35125 (2005).

  63. 63

    Reynolds, C. H. et al. Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cγ1, Grb2, and Src family kinases. J. Biol. Chem. 283, 18177–18186 (2008).

  64. 64

    Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010). This study identified the acetylation of tau and demonstrated that this post-translational modification may contribute to tau pathology.

  65. 65

    Cook, C. et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum. Mol. Genet. 23, 104–116 (2014).

  66. 66

    Cohen, T. J., Friedmann, D., Hwang, A. W., Marmorstein, R. & Lee, V. M. The microtubule-associated tau protein has intrinsic acetyltransferase activity. Nat. Struct. Mol. Biol. 20, 756–762 (2013).

  67. 67

    Irwin, D. J. et al. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am. J. Pathol. 183, 344–351 (2013).

  68. 68

    Min, S. W. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 21, 1154–1162 (2015).

  69. 69

    Martin, L., Latypova, X. & Terro, F. Post-translational modifications of tau protein: implications for Alzheimer's disease. Neurochem. Int. 58, 458–471 (2011).

  70. 70

    Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease. Nat. Med. 2, 871–875 (1996).

  71. 71

    Liu, F., Zaidi, T., Iqbal, K., Grundke-Iqbal, I. & Gong, C. X. Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5. Neuroscience 115, 829–837 (2002).

  72. 72

    Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W. & Gong, C. X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc. Natl Acad. Sci. USA 101, 10804–10809 (2004).

  73. 73

    Yuzwa, S. A., Cheung, A. H., Okon, M., McIntosh, L. P. & Vocadlo, D. J. O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers. J. Mol. Biol. 426, 1736–1752 (2014).

  74. 74

    Yan, S. D. et al. Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide. Nat. Med. 1, 693–699 (1995).

  75. 75

    Watanabe, A. et al. Molecular aging of tau: disulfide-independent aggregation and non-enzymatic degradation in vitro and in vivo. J. Neurochem. 90, 1302–1311 (2004). The authors show that site-specific deamidation or isomerization and non-enzymatic degradation of ageing tau facilitates tau aggregation and can cause the smearing of PHFs on western blot that is typical of AD-tau.

  76. 76

    Ledesma, M. D., Bonay, P. & Avila, J. Tau protein from Alzheimer's disease patients is glycated at its tubulin-binding domain. J. Neurochem. 65, 1658–1664 (1995).

  77. 77

    Reyes, J. F., Geula, C., Vana, L. & Binder, L. I. Selective tau tyrosine nitration in non-AD tauopathies. Acta Neuropathol. 123, 119–132 (2012).

  78. 78

    Funk, K. E. et al. Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity. Biochem. J. 462, 77–88 (2014).

  79. 79

    Shimura, H., Schwartz, D., Gygi, S. P. & Kosik, K. S. CHIP–Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J. Biol. Chem. 279, 4869–4876 (2004).

  80. 80

    Petrucelli, L. et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13, 703–714 (2004).

  81. 81

    Babu, J. R., Geetha, T. & Wooten, M. W. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 94, 192–203 (2005).

  82. 82

    Nathan, J. A., Kim, H. T., Ting, L., Gygi, S. P. & Goldberg, A. L. Why do cellular proteins linked to K63-polyubiquitin chains not associate with proteasomes? EMBO J. 32, 552–565 (2013).

  83. 83

    Dorval, V. & Fraser, P. E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J. Biol. Chem. 281, 9919–9924 (2006).

  84. 84

    Pountney, D. L. et al. SUMO-1 marks the nuclear inclusions in familial neuronal intranuclear inclusion disease. Exp. Neurol. 184, 436–446 (2003).

  85. 85

    Luo, H. B. et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc. Natl Acad. Sci. USA 111, 16586–16591 (2014).

  86. 86

    Corsetti, V. et al. NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. Hum. Mol. Genet. 24, 3058–3081 (2015).

  87. 87

    Garg, S., Timm, T., Mandelkow, E. M., Mandelkow, E. & Wang, Y. Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment. Neurobiol. Aging 32, 1–14 (2011).

  88. 88

    Derisbourg, M. et al. Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci. Rep. 5, 9659 (2015).

  89. 89

    Drubin, D. G., Caput, D. & Kirschner, M. W. Studies on the expression of the microtubule-associated protein, tau, during mouse brain development, with newly isolated complementary DNA probes. J. Cell Biol. 98, 1090–1097 (1984).

  90. 90

    Papasozomenos, S. C. & Binder, L. I. Phosphorylation determines two distinct species of Tau in the central nervous system. Cell. Motil. Cytoskeleton 8, 210–226 (1987).

  91. 91

    Sultan, A. et al. Nuclear tau, a key player in neuronal DNA protection. J. Biol. Chem. 286, 4566–4575 (2011).

  92. 92

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

  93. 93

    Aronov, S., Aranda, G., Behar, L. & Ginzburg, I. Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. J. Neurosci. 21, 6577–6587 (2001).

  94. 94

    Morita, T. & Sobue, K. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR–p70S6K pathway. J. Biol. Chem. 284, 27734–27745 (2009).

  95. 95

    Hirokawa, N., Funakoshi, T., Sato-Harada, R. & Kanai, Y. Selective stabilization of tau in axons and microtubule-associated protein 2C in cell bodies and dendrites contributes to polarized localization of cytoskeletal proteins in mature neurons. J. Cell Biol. 132, 667–679 (1996).

  96. 96

    Kosik, K. S., Crandall, J. E., Mufson, E. J. & Neve, R. L. Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann. Neurol. 26, 352–361 (1989).

  97. 97

    Li, X. et al. Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration. EMBO J. 30, 4825–4837 (2011). This study identifies an axonal sorting mechanism of tau at the axonal initial segment.

  98. 98

    Feinstein, S. C. & Wilson, L. 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 (2005).

  99. 99

    Mandelkow, E. M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med. 2, a006247 (2012).

  100. 100

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

  101. 101

    Dixit, R., Ross, J. L., Goldman, Y. E. & Holzbaur, E. L. Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089 (2008).

  102. 102

    Vershinin, M., Carter, B. C., Razafsky, D. S., King, S. J. & Gross, S. P. Multiple-motor based transport and its regulation by Tau. Proc. Natl Acad. Sci. USA 104, 87–92 (2007).

  103. 103

    Konzack, S., Thies, E., Marx, A., Mandelkow, E. M. & Mandelkow, E. Swimming against the tide: mobility of the microtubule-associated protein tau in neurons. J. Neurosci. 27, 9916–9927 (2007).

  104. 104

    Utton, M. A., Noble, W. J., Hill, J. E., Anderton, B. H. & Hanger, D. P. Molecular motors implicated in the axonal transport of tau and α-synuclein. J. Cell Sci. 118, 4645–4654 (2005).

  105. 105

    Kanaan, N. M. et al. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J. Neurosci. 31, 9858–9868 (2011).

  106. 106

    Magnani, E. et al. Interaction of tau protein with the dynactin complex. EMBO J. 26, 4546–4554 (2007).

  107. 107

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

  108. 108

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

  109. 109

    Knops, J. et al. Overexpression of tau in a nonneuronal cell induces long cellular processes. J. Cell Biol. 114, 725–733 (1991).

  110. 110

    Dawson, H. N. et al. Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J. Cell Sci. 114, 1179–1187 (2001).

  111. 111

    Harada, A. et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488–491 (1994). This study established the first tau-knockout transgenic mouse line and found that the deficiency of tau does not cause overt pathology, owing to the compensatory expression of MAP1A.

  112. 112

    Tai, H. C. et al. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer inverted question marks disease. Acta Neuropathol. Commun. 2, 146 (2014).

  113. 113

    Mondragon-Rodriguez, S. et al. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-d-aspartate receptor-dependent tau phosphorylation. J. Biol. Chem. 287, 32040–32053 (2012).

  114. 114

    Frandemiche, M. L. et al. Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-β oligomers. J. Neurosci. 34, 6084–6097 (2014).

  115. 115

    Loomis, P. A., Howard, T. H., Castleberry, R. P. & Binder, L. I. Identification of nuclear tau isoforms in human neuroblastoma cells. Proc. Natl Acad. Sci. USA 87, 8422–8426 (1990).

  116. 116

    Sjoberg, M. K., Shestakova, E., Mansuroglu, Z., Maccioni, R. B. & Bonnefoy, E. Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization. J. Cell Sci. 119, 2025–2034 (2006).

  117. 117

    Fernandez-Nogales, M. et al. Huntington's disease is a four-repeat tauopathy with tau nuclear rods. Nat. Med. 20, 881–885 (2014).

  118. 118

    Gheyara, A. L. et al. Tau reduction prevents disease in a mouse model of Dravet syndrome. Ann. Neurol. 76, 443–456 (2014).

  119. 119

    Holth, J. K. et al. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33, 1651–1659 (2013).

  120. 120

    Leroy, K. et al. Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am. J. Pathol. 181, 1928–1940 (2012).

  121. 121

    DeVos, S. L. et al. Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33, 12887–12897 (2013). This paper demonstrates that treatment with antisense oligonucleotides can reduce tau-induced pathology.

  122. 122

    Lei, P. et al. Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol. Neurodegener. 9, 29 (2014).

  123. 123

    Hong, X. P. et al. Essential role of tau phosphorylation in adult hippocampal neurogenesis. Hippocampus 20, 1339–1349 (2010).

  124. 124

    Fuster-Matanzo, A. et al. Function of tau protein in adult newborn neurons. FEBS Lett. 583, 3063–3068 (2009).

  125. 125

    Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291–295 (2012). This study shows that tau deficiency may cause neurodegeneration by impairing APP-mediated iron export.

  126. 126

    Kimura, T. et al. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Phil. Trans. R. Soc. B 369, 20130144 (2014).

  127. 127

    Ahmed, T. et al. Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion. Neurobiol. Aging 35, 2474–2478 (2014).

  128. 128

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

  129. 129

    Whiteman, I. T. et al. Activated actin-depolymerizing factor/cofilin sequesters phosphorylated microtubule-associated protein during the assembly of Alzheimer-like neuritic cytoskeletal striations. J. Neurosci. 29, 12994–13005 (2009).

  130. 130

    Kouri, N. et al. Novel mutation in MAPT exon 13 (p. N410H) causes corticobasal degeneration. Acta Neuropathol. 127, 271–282 (2014).

  131. 131

    Coppola, G. et al. Evidence for a role of the rare p. A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. Hum. Mol. Genet. 21, 3500–3512 (2012).

  132. 132

    Barghorn, S. et al. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 39, 11714–11721 (2000).

  133. 133

    Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917 (1998). The authors demonstrate that FTDP-17 mutants of tau show reduced microtubule binding and accelerated aggregation.

  134. 134

    Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).

  135. 135

    Jellinger, K. A. et al. PART, a distinct tauopathy, different from classical sporadic Alzheimer disease. Acta Neuropathol. 129, 757–762 (2015).

  136. 136

    Braak, H. & Del Tredici, K. Are cases with tau pathology occurring in the absence of Aβ deposits part of the AD-related pathological process? Acta Neuropathol. 128, 767–772 (2014).

  137. 137

    von Bergen, M. et al. Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure. Proc. Natl Acad. Sci. USA 97, 5129–5134 (2000). This study identifies two hexapeptide motifs (VQIINK and VQIVYK) in tau R2 and R3, with high propensity for β-sheet structure responsible for tau aggregation.

  138. 138

    Sawaya, M. R. et al. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447, 453–457 (2007). This paper reveals that 4–7-residue sequence motifs of neurodegenerative disease-related proteins, including tau, are sufficient to form fibrils composed of steric zippers, formed by two tightly interdigitated β-sheets.

  139. 139

    Khlistunova, I. et al. 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 (2006).

  140. 140

    Goedert, M. et al. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553 (1996). This study demonstrates that tau can be induced to aggregate in vitro with polyanions such as heparan sulfate.

  141. 141

    Wille, H., Drewes, G., Biernat, J., Mandelkow, E. M. & Mandelkow, E. Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J. Cell Biol. 118, 573–584 (1992).

  142. 142

    Hernandez, F., Cuadros, R. & Avila, J. Zeta 14-3-3 protein favours the formation of human tau fibrillar polymers. Neurosci. Lett. 357, 143–146 (2004).

  143. 143

    Giustiniani, J. et al. Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy. Proc. Natl Acad. Sci. USA 111, 4584–4589 (2014).

  144. 144

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

  145. 145

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

  146. 146

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

  147. 147

    Tepper, K. et al. Oligomer formation of tau protein hyperphosphorylated in cells. J. Biol. Chem. 289, 34389–34407 (2014).

  148. 148

    Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652 (2012).

  149. 149

    Zilka, N. et al. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 580, 3582–3588 (2006).

  150. 150

    de Calignon, A. et al. Caspase activation precedes and leads to tangles. Nature 464, 1201–1204 (2010).

  151. 151

    Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 20, 1254–1262 (2014).

  152. 152

    Wang, Y. P., Biernat, J., Pickhardt, M., Mandelkow, E. & Mandelkow, E. M. Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc. Natl Acad. Sci. USA 104, 10252–10257 (2007). The authors show that truncation of tau can accelerate its aggregation in cells and that pro-aggregant truncated tau can seed the aggregation of endogenous tau.

  153. 153

    Fatouros, C. et al. Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity. Hum. Mol. Genet. 21, 3587–3603 (2012).

  154. 154

    Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009). The authors of this study demonstrate the spreading of tau pathology in a mouse model after injection of an AD brain extract.

  155. 155

    Peeraer, E. et al. Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol. Dis. 73, 83–95 (2015).

  156. 156

    Clavaguera, F. et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299–301 (2014).

  157. 157

    Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014). This paper shows that tau may form different prion-like strains, leading to distinct seeding and spreading pattern of tau pathology.

  158. 158

    Zhukareva, V. et al. Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann. Neurol. 49, 165–175 (2001).

  159. 159

    Gomez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease. Ann. Neurol. 41, 17–24 (1997).

  160. 160

    Morsch, R., Simon, W. & Coleman, P. D. Neurons may live for decades with neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 188–197 (1999).

  161. 161

    Andorfer, C. et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J. Neurosci. 25, 5446–5454 (2005).

  162. 162

    Spires-Jones, T. L. et al. In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J. Neurosci. 28, 862–867 (2008).

  163. 163

    Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005). This study describes a regulatable transgenic mouse line of tauopathy, showing that switching off the expression of the transgenic human tau can rescue cognitive deficits despite the continuing presence of tau aggregates, and implying that tau aggregates are not sufficient for neurodegeneration.

  164. 164

    Van der Jeugd, A. et al. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol. 123, 787–805 (2012).

  165. 165

    Sydow, A. et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J. Neurosci. 31, 2511–2525 (2011).

  166. 166

    Alonso Adel, C., Li, B., Grundke-Iqbal, I. & Iqbal, K. Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl Acad. Sci. USA 103, 8864–8869 (2006).

  167. 167

    Walsh, D. M. & Selkoe, D. J. Aβ oligomers — a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).

  168. 168

    Lasagna-Reeves, C. A. et al. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 26, 1946–1959 (2012).

  169. 169

    Maeda, S. et al. Granular tau oligomers as intermediates of tau filaments. Biochemistry 46, 3856–3861 (2007).

  170. 170

    Tian, H. et al. Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. Int. J. Cell Biol. 2013, 260787 (2013).

  171. 171

    Flach, K. et al. Tau oligomers impair artificial membrane integrity and cellular viability. J. Biol. Chem. 287, 43223–43233 (2012).

  172. 172

    Rizzu, P. et al. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am. J. Hum. Genet. 64, 414–421 (1999).

  173. 173

    Mocanu, M. M. et al. The potential for β-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 (2008). This paper demonstrates that the propensity for β-structure in one hexapeptide motif of pro-aggregant tau can cause neurodegeneration that can be reversed by blocking tau expression or by blocking aggregation using anti-aggregant tau.

  174. 174

    Eckermann, K. et al. The β-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J. Biol. Chem. 282, 31755–31765 (2007).

  175. 175

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

  176. 176

    Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153–4170 (2009).

  177. 177

    Fulga, T. A. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9, 139–148 (2007).

  178. 178

    Guthrie, C. R., Schellenberg, G. D. & Kraemer, B. C. SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans. Hum. Mol. Genet. 18, 1825–1838 (2009).

  179. 179

    Kraemer, B. C. & Schellenberg, G. D. SUT-1 enables tau-induced neurotoxicity in C. elegans. Hum. Mol. Genet. 16, 1959–1971 (2007).

  180. 180

    Zempel, H. et al. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 32, 2920–2937 (2013). This study shows that Aβ oligomers can induce dendritic missorting of tau, which causes loss of spines and loss of microtubules by the activation of spastin.

  181. 181

    Seward, M. E. et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J. Cell Sci. 126, 1278–1286 (2013).

  182. 182

    Oddo, S. et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421 (2003). This authors of this study generated a mouse model with enhanced aggregation of both Aβ and tau, allowing the study of the interplay between these two types of proteins.

  183. 183

    Decker, J. M. et al. Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca++ dysregulation. Acta Neuropathol. Commun. 3, 23 (2015). This paper demonstrates that tau pathology may cause presynaptic dysfunction at an early stage of neurodegeneration.

  184. 184

    Maphis, N. et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138, 1738–1755 (2015).

  185. 185

    Morimoto, R. I. & Cuervo, A. M. Proteostasis and the aging proteome in health and disease. J. Gerontol. A Biol. Sci. Med. Sci. 69 (Suppl. 1), 33–38 (2014).

  186. 186

    Pooler, A. M., Phillips, E. C., Lau, D. H., Noble, W. & Hanger, D. P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 14, 389–394 (2013). This study demonstrates that the physiological release of tau can be stimulated by neuronal activity.

  187. 187

    Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).

  188. 188

    Johnson, G. V. et al. The tau protein in human cerebrospinal fluid in Alzheimer's disease consists of proteolytically derived fragments. J. Neurochem. 68, 430–433 (1997).

  189. 189

    Yamada, K. et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011). This paper demonstrates the release of tau by neurons, arguing that extracellular tau may be in equilibrium with intracellular tau.

  190. 190

    Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). The authors report the protein and lipid composition of synaptic vesicles. Notably, tau is not among them, arguing against a release of axonal tau via synaptic vesicles.

  191. 191

    Karch, C. M., Jeng, A. T. & Goate, A. M. Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J. Biol. Chem. 287, 42751–42762 (2012).

  192. 192

    Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat. Rev. Mol. Cell Biol. 10, 148–155 (2009).

  193. 193

    Gomez-Ramos, A., Diaz-Hernandez, M., Rubio, A., Miras-Portugal, M. T. & Avila, J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol. Cell. Neurosci. 37, 673–681 (2008).

  194. 194

    Gomez-Ramos, A. et al. Characteristics and consequences of muscarinic receptor activation by tau protein. Eur. Neuropsychopharmacol. 19, 708–717 (2009).

  195. 195

    Guo, J. L. & Lee, V. M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).

  196. 196

    Michel, C. H. et al. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J. Biol. Chem. 289, 956–967 (2014).

  197. 197

    Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013).

  198. 198

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). This paper established the staging of AD on the basis of tau pathology, which is now widely accepted.

  199. 199

    Braak, H. & Braak, E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 92, 197–201 (1996).

  200. 200

    Yan, M. H., Wang, X. & Zhu, X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med. 62, 90–101 (2013).

  201. 201

    Nave, K. A. & Werner, H. B. Myelination of the nervous system: mechanisms and functions. Annu. Rev. Cell Dev. Biol. 30, 503–533 (2014).

  202. 202

    Hyman, B. T., Van Hoesen, G. W., Damasio, A. R. & Barnes, C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168–1170 (1984).

  203. 203

    Hochgrafe, K. et al. Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathol. Commun. 3, 25 (2015).

  204. 204

    Wischik, C. M. et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J. Alzheimers Dis. 44, 705–720 (2015).

  205. 205

    Sievers, S. A. et al. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475, 96–100 (2011). This paper identifies several d-amino acid peptides that can inhibit tau aggregation by interacting with steric zippers formed by the hexapeptide.

  206. 206

    Lovestone, S. et al. A phase II trial of tideglusib in Alzheimer's disease. J. Alzheimers Dis. 45, 75–88 (2015).

  207. 207

    Hoglinger, G. U. et al. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Mov. Disord. 29, 479–487 (2014).

  208. 208

    Boxer, A. L. et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 13, 676–685 (2014).

  209. 209

    Brunden, K. R. et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci. 30, 13861–13866 (2010).

  210. 210

    US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  211. 211

    Blair, L. J., Sabbagh, J. J. & Dickey, C. A. Targeting Hsp90 and its co-chaperones to treat Alzheimer's disease. Expert Opin. Ther. Targets 18, 1219–1232 (2014).

  212. 212

    Karagoz, G. E. et al. Hsp90–Tau complex reveals molecular basis for specificity in chaperone action. Cell 156, 963–974 (2014). This is a structural study that demonstrates the interaction between HSP90 and tau.

  213. 213

    Ozcelik, S. et al. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS ONE 8, e62459 (2013).

  214. 214

    Kruger, U., Wang, Y., Kumar, S. & Mandelkow, E. M. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol. Aging 33, 2291–2305 (2012).

  215. 215

    Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

  216. 216

    Sigurdsson, E. M. Tau immunotherapy and imaging. Neurodegener. Dis. 13, 103–106 (2014).

  217. 217

    Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007). This paper demonstrates that a tau-based active immunotherapy reduces tau pathology and slows progression of behavioural impairment in a line of tau transgenic mice.

  218. 218

    Golde, T. E. Open questions for Alzheimer's disease immunotherapy. Alzheimers Res. Ther. 6, 3 (2014).

  219. 219

    Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013).

  220. 220

    Collin, L. et al. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease. Brain 137, 2834–2846 (2014).

  221. 221

    d'Abramo, C., Acker, C. M., Jimenez, H. T. & Davies, P. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS ONE 8, e62402 (2013).

  222. 222

    Castillo-Carranza, D. L. et al. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014).

  223. 223

    Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013). This study presents a new concept of immunotherapy: targeting extracellular tau seeds with tau-specific antibodies to prevent the spreading of tau pathology.

  224. 224

    Neve, R. L., Harris, P., Kosik, K. S., Kurnit, D. M. & Donlon, T. A. Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res. 387, 271–280 (1986).

  225. 225

    Trabzuni, D. et al. MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum. Mol. Genet. 21, 4094–4103 (2012).

  226. 226

    Boutajangout, A., Boom, A., Leroy, K. & Brion, J. P. Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease. FEBS Lett. 576, 183–189 (2004).

Download references


The authors thank E.-M. Mandelkow for critical reading of and insightful suggestions for the manuscript, and thank L. Krueger for fruitful discussions. The project was supported in part by the German Center for Neurodegenerative Diseases (DZNE), the Max Planck Society (MPG), the Tau Consortium and the Wellcome Trust/MRC Alzheimer Consortium.

Author information

Correspondence to Yipeng Wang or Eckhard Mandelkow.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links



PowerPoint slides


Paired helical filaments

(PHFs). Fibrous polymers of tau that resemble twisted filaments (originally considered to be pairs of filaments, hence the name) of 20 nm width and 80 nm crossover periodicity. Variants of PHFs are the 'straight filaments', which do not have a twisted structure.

Neurofibrillary tangles

(NFTs). Bundles of paired helical filaments in the cytosol of neurons.

Tau aggregation

An interaction between tau molecules that leads to the generation of fibrous polymers with a periodic structure.

Projection domain

The amino-terminal half of tau that projects away from microtubules when tau binds to microtubules.

Assembly domain

The carboxy-terminal portion of tau that is responsible for binding to microtubules.

Lys48 linkages

The binding of a ubiquitin molecule to another ubiquitin via the Lys48 of the seven Lys residues of ubiquitin.

Nucleation–elongation mechanism

A model that postulates that the rate-limiting step for protein aggregation is the formation of an initial oligomeric nucleus for aggregation. Once formed, polymerization can proceed via elongation, whereby protein subunits are directly added to the growing ends of the fibre.

Template-assisted model

A model developed to explain aggregation of prion protein. It proposes that the infectious scrapie prion protein serves as a template that catalyses conformational changes of normal PrPC to PrPSc, leading to PrPSc aggregation.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Mandelkow, E. Tau in physiology and pathology. Nat Rev Neurosci 17, 22–35 (2016). https://doi.org/10.1038/nrn.2015.1

Download citation

Further reading