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  • Review Article
  • Published:

Tau and neurodegenerative disease: the story so far

Key Points

  • Tau pathology, consisting of hyperphosphorylated tau, is a hallmark of Alzheimer disease (AD) and other tauopathies

  • Hyperphosphorylation converts tau from a normal functional protein to a neurotoxic protein, and induces prion-like templating activity

  • Protein phosphatase 2A has key roles in multiple aetiopathogenic mechanisms of sporadic AD

  • Inhibition of hyperphosphorylation and clearance of the pathological tau are promising therapeutic approaches for the tauopathies; in addition, neuroregeneration can rescue both tau pathology and cognitive impairment

  • A phase I clinical trial of an active tau immunization vaccine was recently completed in patients with AD

  • Assays for tau levels in cerebrospinal fluid and plasma are available, and tau radiotracers for PET are under development

Abstract

In 1975, tau protein was isolated as a microtubule-associated factor from the porcine brain. In the previous year, a paired helical filament (PHF) protein had been identified in neurofibrillary tangles in the brains of individuals with Alzheimer disease (AD), but it was not until 1986 that the PHF protein and tau were discovered to be one and the same. In the AD brain, tau was found to be abnormally hyperphosphorylated, and it inhibited rather than promoted in vitro microtubule assembly. Almost 80 disease-causing exonic missense and intronic silent mutations in the tau gene have been found in familial cases of frontotemporal dementia but, to date, no such mutation has been found in AD. The first phase I clinical trial of an active tau immunization vaccine in patients with AD was recently completed. Assays for tau levels in cerebrospinal fluid and plasma are now available, and tau radiotracers for PET are under development. In this article, we provide an overview of the pivotal discoveries in the tau research field over the past 40 years. We also review the current status of the field, including disease mechanisms and therapeutic approaches.

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Figure 1: Timeline of discoveries and advances in the tau research field.
Figure 2: Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD.
Figure 3: Tau as a primary and secondary cause of disease.
Figure 4: Generation of tau seeds and spread of tau pathology.
Figure 5: Key steps in AD neurofibrillary degeneration, and possible therapeutic approaches.

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References

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Tomlinson, B. E., Blessed, G. & Roth, M. Observations on the brains of demented old people. J. Neurol. Sci. 11, 205–242 (1970).

    CAS  PubMed  Google Scholar 

  4. Iqbal, K. et al. Protein changes in senile dementia. Brain Res. 77, 337–343 (1974).

    CAS  PubMed  Google Scholar 

  5. Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).

    CAS  PubMed  Google Scholar 

  6. Iqbal, K. et al. Defective brain microtubule assembly in Alzheimer's disease. Lancet 2, 421–426 (1986).

    CAS  PubMed  Google Scholar 

  7. Goedert, M., Spillantini, M. G., Potier, M. C., Ulrich, J. & Crowther, R. A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 8, 393–399 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Drubin, D. G. & Kirschner, M. W. Tau protein function in living cells. J. Cell Biol. 103, 2739–2746 (1986).

    CAS  PubMed  Google Scholar 

  9. Lee, G. et al. Phosphorylation of tau by fyn: implications for Alzheimer's disease. J. Neurosci. 24, 2304–2312 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Roberson, E. D. et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J. Neurosci. 31, 700–711 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305 (1984).

    CAS  PubMed  Google Scholar 

  12. Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 5562–5566 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Iqbal, K. & Tellez-Nagel, I. Isolation of neurons and glial cells from normal and pathological human brains. Brain Res. 45, 296–301 (1972).

    CAS  PubMed  Google Scholar 

  14. Cleveland, D. W., Hwo, S. Y. & Kirschner, M. W. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207–225 (1977).

    CAS  PubMed  Google Scholar 

  15. Grundke-Iqbal, I., Johnson, A. B., Wisniewski, H. M., Terry, R. D. & Iqbal, K. Evidence that Alzheimer neurofibrillary tangles originate from neurotubules. Lancet 1, 578–580 (1979).

    CAS  PubMed  Google Scholar 

  16. Grundke-Iqbal, I., Johnson, A. B., Terry, R. D., Wisniewski, H. M. & Iqbal, K. Alzheimer neurofibrillary tangles: antiserum and immunohistological staining. Ann. Neurol. 6, 532–537 (1979).

    CAS  PubMed  Google Scholar 

  17. Iqbal, K., Zaidi, T., Thompson, C. H., Merz, P. A. & Wisniewski, H. M. Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol. 62, 167–177 (1984).

    CAS  PubMed  Google Scholar 

  18. Grundke-Iqbal, I., Iqbal, K., Tung, Y. C. & Wisniewski, H. M. Alzheimer paired helical filaments: immunochemical identification of polypeptides. Acta Neuropathol. 62, 259–267 (1984).

    CAS  PubMed  Google Scholar 

  19. Wang, G. P., Grundke-Iqbal, I., Kascsak, R. J., Iqbal, K. & Wisniewski, H. M. Alzheimer neurofibrillary tangles: monoclonal antibodies to inherent antigen(s). Acta Neuropathol. 62, 268–275 (1984).

    CAS  PubMed  Google Scholar 

  20. Mehta, P. D., Thal, L., Wisniewski, H. M., Grundke-Iqbal, I. & Iqbal, K. Paired helical filament antigen in CSF. Lancet 2, 35 (1985).

    CAS  PubMed  Google Scholar 

  21. Braak, H., Braak, E., Grundke-Iqbal, I. & Iqbal, K. Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65, 351–355 (1986).

    CAS  PubMed  Google Scholar 

  22. Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 477, 90–99 (1989).

    CAS  PubMed  Google Scholar 

  23. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  24. Lee, G., Cowan, N. & Kirschner, M. The primary structure and heterogeneity of tau protein from mouse brain. Science 239, 285–288 (1988).

    CAS  PubMed  Google Scholar 

  25. Himmler, A., Drechsel, D., Kirschner, M. W. & Martin, D. W. Jr. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell. Biol. 9, 1381–1388 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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, 352–261 (1989).

    CAS  PubMed  Google Scholar 

  27. Novak, M., Kabat, J. & Wischik, C. M. Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J. 12, 365–370 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. Hasegawa, M. et al. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J. Biol. Chem. 267, 17047–17054 (1992).

    CAS  PubMed  Google Scholar 

  30. Hanger, D. P., Betts, J. C., Loviny, T. L., Blackstock, W. P. & Anderton, B. H. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71, 2465–2476 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61, 765–772 (1994).

    CAS  PubMed  Google Scholar 

  33. Gong, C. X. et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J. Neurochem. 65, 732–738 (1995).

    CAS  PubMed  Google Scholar 

  34. Tanimukai, H., Grundke-Iqbal, I. & Iqbal, K. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. Am. J. Pathol. 166, 1761–1771 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsujio, I. et al. Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau. FEBS Lett. 579, 363–372 (2005).

    CAS  PubMed  Google Scholar 

  36. Bolognin, S. et al. An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol. 123, 133–151 (2012).

    CAS  PubMed  Google Scholar 

  37. Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y. C., Liu, F. & Iqbal, K. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J. Biol. Chem. 288, 17495–17507 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, X. et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol. 127, 243–256 (2014).

    CAS  PubMed  Google Scholar 

  39. Arif, M., Kazim, S. F., Grundke-Iqbal, I., Garruto, R. M. & Iqbal, K. Tau pathology involves protein phosphatase 2A in parkinsonism–dementia of Guam. Proc. Natl Acad. Sci. USA 111, 1144–1149 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Khatoon, S., Grundke-Iqbal, I. & Iqbal, K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein. J. Neurochem. 59, 750–753 (1992).

    CAS  PubMed  Google Scholar 

  41. Vandermeeren, M. et al. Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J. Neurochem. 61, 1828–1834 (1993).

    CAS  PubMed  Google Scholar 

  42. Kopke, 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Alonso, A. D., Mederlyova, A., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873–34881 (2004).

    Google Scholar 

  46. Alonso, A. C., Grundke-Iqbal, I. & Iqbal, K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 2, 783–787 (1996).

    CAS  PubMed  Google Scholar 

  47. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Encouraging results of AXON's tau vaccine advance Alzheimer's therapy. AXON Neuroscience [online], (2015).

  51. 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).

    CAS  PubMed  Google Scholar 

  52. Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998).

    CAS  PubMed  Google Scholar 

  54. Ghetti, B. et al. Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol. Appl. Neurobiol. 41, 24–46 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lu, M. & Kosik, K. S. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol. Biol. Cell 12, 171–184 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Sengupta, A., Grundke-Iqbal, I. & Iqbal, K. Regulation of phosphorylation of tau by protein kinases in rat brain. Neurochem. Res. 31, 1473–1480 (2006).

    CAS  PubMed  Google Scholar 

  57. Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 (1999).

    CAS  PubMed  Google Scholar 

  58. Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).

    PubMed  Google Scholar 

  59. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

    CAS  PubMed  Google Scholar 

  60. Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Iqbal, K. et al. Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers. Ann. Neurol. 58, 748–757 (2005).

    CAS  PubMed  Google Scholar 

  62. Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094–1108 (2013).

    CAS  PubMed  Google Scholar 

  63. Fodero-Tavoletti, M. T. et al. 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. Brain 134, 1089–1100 (2011).

    PubMed  Google Scholar 

  64. Okamura, N. et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J. Nucl. Med. 54, 1420–1427 (2013).

    CAS  PubMed  Google Scholar 

  65. Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34, 457–468 (2013).

    CAS  PubMed  Google Scholar 

  66. Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J. Alzheimers Dis. 38, 171–184 (2014).

    PubMed  Google Scholar 

  67. Ksiezak-Reding, H., Liu, W. K. & Yen, S. H. Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments. Brain Res. 597, 209–219 (1992).

    CAS  PubMed  Google Scholar 

  68. Morishima-Kawashima, M. et al. Proline-directed and non-proline-directed phosphorylation of PHF-tau. J. Biol. Chem. 270, 823–829 (1995).

    CAS  PubMed  Google Scholar 

  69. Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 1641–1644 (1987).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Grundke-Iqbal, I. et al. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res. 464, 43–52 (1988).

    CAS  PubMed  Google Scholar 

  72. Cripps, D. et al. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J. Biol. Chem. 281, 10825–10838 (2006).

    CAS  PubMed  Google Scholar 

  73. Wischik, C. M. et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4884–4888 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Gamblin, T. C. et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc. Natl Acad. Sci. USA 100, 10032–10037 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ledesma, M. D., Bonay, P., Colaco, C. & Avila, J. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269, 21614–21619 (1994).

    CAS  PubMed  Google Scholar 

  77. Smith, M. A. et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc. Natl Acad. Sci. USA 91, 5710–5714 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Reynolds, M. R. et al. Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies. J. Neurosci. 26, 10636–10645 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Odetti, P. et al. Lipoperoxidation is selectively involved in progressive supranuclear palsy. J. Neuropathol. Exp. Neurol. 59, 393–397 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Cohen, T. J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2, 252 (2011).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res. Mol. Brain Res. 38, 200–208 (1996).

    CAS  PubMed  Google Scholar 

  87. Alonso, A. D., Grundke-Iqbal, I., Barra, H. S. & Iqbal, K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl Acad. Sci. USA 94, 298–303 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Alonso, A. D. et al. Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J. Biol. Chem. 276, 37967–37973 (2001).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  91. Kontsekova, E., Zilka, N., Kovacech, B., Novak, P. & Novak, M. First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model. Alzheimers Res. Ther. 6, 44 (2014).

    PubMed  PubMed Central  Google Scholar 

  92. Arnold, C. S. et al. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J. Biol. Chem. 271, 28741–28744 (1996).

    CAS  PubMed  Google Scholar 

  93. Yuzwa, S. A. et al. Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody. Amino Acids 40, 857–868 (2011).

    CAS  PubMed  Google Scholar 

  94. Liu, F. et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820–1832 (2009).

    PubMed  PubMed Central  Google Scholar 

  95. Gong, C. X., Liu, F., Grundke-Iqbal, I. & Iqbal, K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J. Alzheimers Dis. 9, 1–12 (2006).

    CAS  PubMed  Google Scholar 

  96. Liu, Y., Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C. X. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J. Neurochem. 111, 242–249 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ishiguro, K. et al. Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267, 10897–10901 (1992).

    CAS  PubMed  Google Scholar 

  98. Arioka, M. et al. Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. J. Neurochem. 60, 461–468 (1993).

    CAS  PubMed  Google Scholar 

  99. Liu, F. et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Woods, Y. L. et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bε at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Baudier, J. & Cole, R. D. Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 263, 5876–5883 (1988).

    CAS  PubMed  Google Scholar 

  102. Ledesma, M. D., Correas, I., Avila, J. & Díaz-Nido, J. Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease. FEBS Lett. 308, 218–224 (1992).

    CAS  PubMed  Google Scholar 

  103. Singh, T. J., Grundke-Iqbal, I. & Iqbal, K. Differential phosphorylation of human tau isoforms containing three repeats by several protein kinases. Arch. Biochem. Biophys. 328, 43–50 (1996).

    CAS  PubMed  Google Scholar 

  104. Singh, T. J., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. Mol. Cell. Biochem. 154, 143–151 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. Sironi, J. J. et al. Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. FEBS Lett. 436, 471–475 (1998).

    CAS  PubMed  Google Scholar 

  107. Singh, T. J., Haque, N., Grundke-Iqbal, I. & Iqbal, K. Rapid Alzheimer-like phosphorylation of tau by the synergistic actions of non-proline-dependent protein kinases and GSK-3. FEBS Lett. 358, 267–272 (1995).

    CAS  PubMed  Google Scholar 

  108. Singh, T. J., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases. FEBS Lett. 358, 4–8 (1995).

    CAS  PubMed  Google Scholar 

  109. Sengupta, A. et al. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch. Biochem. Biophys. 357, 299–309 (1998).

    CAS  PubMed  Google Scholar 

  110. Sengupta, A., Wu, Q., Grundke-Iqbal, I., Iqbal, K. & Singh, T. J. Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol. Cell. Biochem. 167, 99–105 (1997).

    CAS  PubMed  Google Scholar 

  111. Liu, F. et al. PKA modulates GSK-3β- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. FEBS Lett. 580, 6269–6274 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Yamaguchi, H. et al. Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 92, 232–241 (1996).

    CAS  PubMed  Google Scholar 

  113. Pei, J. J. et al. Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration. Brain Res. 797, 267–277 (1998).

    CAS  PubMed  Google Scholar 

  114. Pei, J. J. et al. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J. Neuropathol. Exp. Neurol. 58, 1010–1019 (1999).

    CAS  PubMed  Google Scholar 

  115. Pei, J. J. et al. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. J. Alzheimers Dis. 3, 41–48 (2001).

    CAS  PubMed  Google Scholar 

  116. Jin, N. et al. Truncation and activation of dual specificity tyrosine phosphorylation-regulated kinase 1A by calpain I: a molecular mechanism linked to tau pathology in Alzheimer disease. J. Biol. Chem. 290, 15219–15237 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Jin, N. et al. Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease. Sci. Rep. 5, 8187 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gong, C. X. et al. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J. Biol. Chem. 275, 5535–5544 (2000).

    CAS  PubMed  Google Scholar 

  119. Bennecib, M., Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett. 485, 87–93 (2000).

    CAS  PubMed  Google Scholar 

  120. Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C. X. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942–1950 (2005).

    PubMed  Google Scholar 

  121. Iqbal, K. et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198–210 (2005).

    CAS  PubMed  Google Scholar 

  122. Sengupta, A., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett. 580, 5925–5933 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Qian, W. & Liu, F. Regulation of alternative splicing of tau exon 10. Neurosci. Bull. 30, 367–377 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Virshup, D. M. Protein phosphatase 2A: a panoply of enzymes. Curr. Opin. Cell Biol. 12, 180–185 (2000).

    CAS  PubMed  Google Scholar 

  125. McCright, B., Brothman, A. R. & Virshup, D. M. Assignment of human protein phosphatase 2A regulatory subunit genes B56α, B56β, B56γ, B56δ, and B56ε (PPP2R5A–PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 → p12. Genomics 36, 168–170 (1996).

    CAS  PubMed  Google Scholar 

  126. McCright, B. & Virshup, D. M. Identification of a new family of protein phosphatase 2A regulatory subunits. J. Biol. Chem. 270, 26123–26128 (1995).

    CAS  PubMed  Google Scholar 

  127. Chen, J., Martin, B. L. & Brautigan, D. L. Regulation of protein serine–threonine phosphatase type-2A by tyrosine phosphorylation. Science 257, 1261–1264 (1992).

    CAS  PubMed  Google Scholar 

  128. Lee, J. & Stock, J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. J. Biol. Chem. 268, 19192–19195 (1993).

    CAS  PubMed  Google Scholar 

  129. Lee, J., Chen, Y., Tolstykh, T. & Stock, J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc. Natl Acad. Sci. USA 93, 6043–6047 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Tolstykh, T., Lee, J., Vafai, S. & Stock, J. B. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. EMBO J. 19, 5682–5691 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Wu, J. et al. Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo. EMBO J. 19, 5672–5681 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Longin, S. et al. Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic subunit. J. Biol. Chem. 282, 26971–26980 (2007).

    CAS  PubMed  Google Scholar 

  133. Li, M., Lyon, M. K. & Garcea, R. L. In vitro phosphorylation of the polyomavirus major capsid protein VP1 on serine 66 by casein kinase II. J. Biol. Chem. 270, 26006–26011 (1995).

    CAS  PubMed  Google Scholar 

  134. Li, M., Makkinje, A. & Damuni, Z. Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 35, 6998–7002 (1996).

    CAS  PubMed  Google Scholar 

  135. Li, M., Makkinje, A. & Damuni, Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J. Biol. Chem. 271, 11059–11062 (1996).

    CAS  PubMed  Google Scholar 

  136. Campion, D. et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65, 664–670 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    CAS  PubMed  Google Scholar 

  138. Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    CAS  PubMed  Google Scholar 

  139. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    CAS  PubMed  Google Scholar 

  140. Halfon, S., Patel, S., Vega, F., Zurawski, S. & Zurawski, G. Autocatalytic activation of human legumain at aspartic acid residues. FEBS Lett. 438, 114–118 (1998).

    CAS  PubMed  Google Scholar 

  141. Li, D. N., Matthews, S. P., Antoniou, A. N., Mazzeo, D. & Watts, C. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J. Biol. Chem. 278, 38980–38990 (2003).

    CAS  PubMed  Google Scholar 

  142. Liu, Z. et al. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol. Cell 29, 665–678 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Arnaud, L. et al. Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2PP2A/SET. FEBS Lett. 585, 2653–2659 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  145. Murch, S. J., Cox, P. A. & Banack, S. A. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc. Natl Acad. Sci. USA 101, 12228–12231 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Pablo, J. et al. Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol. Scand. 120, 216–225 (2009).

    CAS  PubMed  Google Scholar 

  147. Liang, Z. et al. Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome. J. Alzheimers Dis. 13, 295–302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Iqbal, K., Zaidi, T., Bancher, C. & Grundke-Iqbal, I. Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett. 349, 104–108 (1994).

    CAS  PubMed  Google Scholar 

  149. Alonso, A. D., Li, B., Grundke-Iqbal, I. & Iqbal, K. Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl Acad. Sci. USA 23, 8864–8869 (2006).

    Google Scholar 

  150. Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain. Nat. Commun. 6, 8490 (2015).

    CAS  PubMed  Google Scholar 

  151. Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Khan, U. A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat. Neurosci. 17, 304–311 (2014).

    CAS  PubMed  Google Scholar 

  153. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Reiman, E. M. et al. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 26 (Suppl. 3), 321–329 (2011).

    PubMed  PubMed Central  Google Scholar 

  157. Moulder, K. L. et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res. Ther. 5, 48 (2013).

    PubMed  PubMed Central  Google Scholar 

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

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

    CAS  PubMed  Google Scholar 

  160. Forlenza, O. V., De-Paula, V. J. & Diniz, B. S. Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Tariot, P. N. et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch. Gen. Psychiatry 68, 853–861 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Basurto-Islas, G. et al. Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease. Neurobiol. Aging 35, 2701–2712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Kickstein, E. et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc. Natl Acad. Sci. USA 107, 21830–21835 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. van Eersel, J. et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc. Natl Acad. Sci. USA 107, 13888–13893 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Yuzwa, S. A. et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat. Chem. Biol. 4, 483–490 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  167. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Shibuya, Y. et al. Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol. Aging 36, 2248–2259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Harrington, C. R. et al. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer disease. J. Biol. Chem. 290, 10862–10875 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 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).

    PubMed  PubMed Central  Google Scholar 

  171. Wischik, C. M., Harrington, C. R. & Storey, J. M. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem. Pharmacol. 88, 529–539 (2014).

    CAS  PubMed  Google Scholar 

  172. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  173. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

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

  175. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Chai, X. et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457–34467 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    PubMed  PubMed Central  Google Scholar 

  179. Dai, C. L. et al. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J. Neural Transm. (Vienna) 122, 607–617 (2015).

    CAS  Google Scholar 

  180. Funk, K. E., Mirbaha, H., Jiang, H., Holtzman, D. M. & Diamond, M. I. Distinct therapeutic mechanisms of Tau antibodies: promoting microglial clearance versus blocking neuronal uptake. J. Biol. Chem. 290, 21652–21662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer's disease. Trends Mol. Med. 21, 394–402 (2015).

    CAS  PubMed  Google Scholar 

  182. Zhang, B. et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl Acad. Sci. USA 102, 227–231 (2005).

    CAS  PubMed  Google Scholar 

  183. Gozes, I., Schirer, Y., Idan-Feldman, A., David, M. & Furman-Assaf, S. NAP alpha-aminoisobutyric acid (IsoNAP). J. Mol. Neurosci. 52, 1–9 (2014).

    CAS  PubMed  Google Scholar 

  184. Li, B. et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J. Neuropathol. Exp. Neurol. 67, 78–84 (2008).

    CAS  PubMed  Google Scholar 

  185. Kazim, S. F. et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 71, 110–130 (2014).

    CAS  PubMed  Google Scholar 

  186. Blanchard, J. et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice. Acta Neuropathol. 120, 605–621 (2010).

    CAS  PubMed  Google Scholar 

  187. Chohan, M. O. et al. Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol. Aging 32, 1420–1434 (2011).

    CAS  PubMed  Google Scholar 

  188. Bolognin, S., Buffelli, M., Puolivali, J. & Iqbal, K. Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound. Neurobiol. Aging 35, 2134–2146 (2014).

    CAS  PubMed  Google Scholar 

  189. Rosenmann, H. et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch. Neurol. 63, 1459–1467 (2006).

    PubMed  Google Scholar 

  190. Brion, J. P., Couck, A. M., Passareiro, E. & Flament-Durand, J. Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J. Submicrosc. Cytol. 17, 89–96 (1985).

    CAS  PubMed  Google Scholar 

  191. Delacourte, A. & Defossez, A. Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J. Neurol. Sci. 76, 173–186 (1986).

    CAS  PubMed  Google Scholar 

  192. Ihara, Y., Nukina, N., Miura, R. & Ogawara, M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J. Biochem. 99, 1807–1810 (1986).

    CAS  PubMed  Google Scholar 

  193. Kosik, K. S., Joachim, C. L. & Selkoe, D. J. Microtubule-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044–4048 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Spillantini, M. G. et al. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc. Natl Acad. Sci. USA 94, 4113–4118 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917 (1998).

    CAS  PubMed  Google Scholar 

  196. Maeda, S. et al. Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease. Neurosci. Res. 54, 197–201 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  198. Shi, J. et al. Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. J. Biol. Chem. 283, 28660–28669 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Chen, Y. et al. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice. Front. Aging Neurosci. 6, 100 (2014).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are most grateful to Ezzat El-Akkad for his help in preparation of figures, and to Janet Murphy for secretarial assistance. For seminal discoveries and advances, input was sought from several leaders in the field, including Jesús Avila, Michel Goedert, Maria Spillantini, Eva Maria Mandelkow, Eckhard Mandelkow, Jürgen Götz, Michal Novak, Virginia M. Lee, John Trojanowski, Luc Buee, Akihiko Takashima and Kenneth Kosik. K.I., F.L. and C.-X.G. work for the New York State Office for People with Developmental Disabilities (NYS OPWDD).

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Khalid Iqbal.

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K.I. serves on the scientific advisory board of AXON Neuroscience, has received research grants from Ever NeuroPharma and Signum Biosciences, and holds several patents on treatment of Alzheimer disease and related conditions. C.-X.G. serves on the scientific advisory board of Alectos Therapeutics. F.L. declares no competing interests.

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Iqbal, K., Liu, F. & Gong, CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12, 15–27 (2016). https://doi.org/10.1038/nrneurol.2015.225

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