Advertisement

Emerging Diagnostic and Therapeutic Strategies for Tauopathies

  • David Coughlin
  • David J. Irwin
Dementia (K Marder, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dementia

Abstract

Purpose of Review

Tauopathies represent a spectrum of incurable and progressive age-associated neurodegenerative diseases that currently are diagnosed definitively only at autopsy. Few clinical diagnoses, such as classic Richardson’s syndrome of progressive supranuclear palsy, are specific for underlying tauopathy and no clinical syndrome is fully sensitive to reliably identify all forms of clinically manifest tauopathy. Thus, a major unmet need for the development and implementation of tau-targeted therapies is precise antemortem diagnosis. This article reviews new and emerging diagnostic therapies for tauopathies including novel imaging techniques and biomarkers and also reviews recent tau therapeutics.

Recent Findings

Building evidence from animal and cell models suggests that prion-like misfolding and propagation of pathogenic tau proteins between brain cells are central to the neurodegenerative process. These rapidly growing developments build rationale and motivation for the development of therapeutics targeting this mechanism through altering phosphorylation and other post-translational modifications of the tau protein, blocking aggregation and spread using small molecular compounds or immunotherapy and reducing or silencing expression of the MAPT tau gene.

Summary

New clinical criteria, CSF, MRI, and PET biomarkers will aid in identifying tauopathies earlier and more accurately which will aid in selection for new clinical trials which focus on a variety of agents including immunotherapy and gene silencing.

Keywords

Tauopathy Progressive supranuclear palsy Alzheimer’s disease Immunotherapy Gene therapy Tau-PET 

Notes

Acknowledgements

David Coughlin is supported by the Penn Institute for Translational Medicine and Therapeutics and David J. Irwin is supported by NIH grant K23NS088341, Brightfocus Foundation A2016244S and the Penn Institute on Aging. We thank the patients and their families who participated in brain donation and clinical research reviewed in this manuscript for without their time and effort, these advances would not be possible.

Compliance with Ethical Standards

Conflict of Interest

David Coughlin declares that he has no conflict of interest.

David J. Irwin reports other from GE Healthcare.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance

  1. 1.
    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. 1990;9(13):4225.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol. 2012;123(1):1–11.PubMedCrossRefGoogle Scholar
  3. 3.
    •• Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science. 1991;251(4994):675–8. This is the first description of tau being the major constituent of tangle pathology in Alzheimer’s disease PubMedCrossRefGoogle Scholar
  4. 4.
    Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362–81.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathologica. 2014.Google Scholar
  6. 6.
    Duyckaerts C, Braak H, Brion JP, Buee L, Del Tredici K, Goedert M, et al. PART is part of Alzheimer disease. Acta Neuropathol. 2015;129(5):749–56.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Irwin DJ, Lee VM, Trojanowski JQ. Parkinson’s disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat rev Neurosc 2013.Google Scholar
  8. 8.
    Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. The Lancet Neurology. 2017;16(1):55–65.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    •• Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119(1):1–4. Current neuropathological criteria for FTLD-Tau PubMedCrossRefGoogle Scholar
  10. 10.
    Boxer AL, Gold M, Huey E, Hu WT, Rosen H, Kramer J, et al. The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier). Alzheimer's & Dementia: the Journal of the Alzheimer's Association. 2012.Google Scholar
  11. 11.
    Irwin DJ, Brettschneider J, McMillan CT, Cooper F, Olm C, Arnold SE, et al. Deep clinical and neuropathological phenotyping of Pick disease. Ann Neurol. 2016;79(2):272–87.PubMedCrossRefGoogle Scholar
  12. 12.
    Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain : a journal of neurology. 2007;130(Pt 6):1566–76.CrossRefGoogle Scholar
  13. 13.
    Forman M, Trojanoswki JQ, Lee VM-Y. In: Esiri M, Lee VM-Y, JQ T, editors. Hereditary tauopathies and idiopathic frontotemporal dementias. 2nd ed. Cambridge: Cambridge University Press; 2004.Google Scholar
  14. 14.
    • Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–13. Novel in vivo data for transmission hypothesis of tau in murine model PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2013;33(3):1024–37.CrossRefGoogle Scholar
  16. 16.
    Guo JL, Lee VM. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett. 2013;587(6):717–23.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.PubMedCrossRefGoogle Scholar
  18. 18.
    Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110(23):9535–40.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol. 2015;129(2):221–37.PubMedCrossRefGoogle Scholar
  20. 20.
    Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82(6):1271–88.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, et al. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron. 2016;92(4):796–812.PubMedCrossRefGoogle Scholar
  22. 22.
    Bolton DC, McKinley MP, Prusiner SB. Identification of a protein that purifies with the scrapie prion. Science. 1982;218(4579):1309–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, et al. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA neurology. 2013;70(4):462–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53(3):337–51.PubMedCrossRefGoogle Scholar
  25. 25.
    • Guo JL, Lee VM. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 2014;20(2):130–8. Comprehensive review of transmission studies in neurodegenerative disease PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Passamonti L, Vazquez Rodriguez P, Hong YT, Allinson KS, Williamson D, Borchert RJ, et al. 18F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy. Brain : a journal of neurology. 2017;140(3):781–91.Google Scholar
  27. 27.
    Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL. Rapidly progressive dementia. Ann Neurol. 2008;64(1):97–108.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW. Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta. 2005;1739(2–3):216–23.PubMedCrossRefGoogle Scholar
  29. 29.
    Schmidt ML, Schuck T, Sheridan S, Kung MP, Kung H, Zhuang ZP, et al. The fluorescent Congo red derivative, (trans, trans)-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse beta-pleated sheet structures in postmortem human neurodegenerative disease brains. Am J Pathol. 2001;159(3):937–43.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Irwin DJ, Cohen TJ, Grossman M, Arnold SE, Xie SX, Lee VM, et al. Acetylated tau, a novel pathological signature in Alzheimer’s disease and other tauopathies. Brain: a Journal of Neurology. 2012;135(Pt 3):807–18.CrossRefGoogle Scholar
  31. 31.
    Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain: a Journal of Neurology. 2011;134(Pt 9):2456–77.CrossRefGoogle Scholar
  32. 32.
    Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496–503.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006–14.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    • Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM, et al. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol. 2015;129(4):469–91. Comprehensive review of clinicopathological correlations in FTLD PubMedCrossRefGoogle Scholar
  35. 35.
    Dickson DW, Kouri N, Murray ME, Josephs KA. Neuropathology of frontotemporal lobar degeneration-tau (FTLD-Tau). Journal of molecular neuroscience : MN. 2011;45(3):384–9.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Wolfe MS. The role of tau in neurodegenerative diseases and its potential as a therapeutic target. Scientifica. 2012;2012.Google Scholar
  37. 37.
    Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011;43(7):699–705.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47(1):1–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Respondek G, Stamelou M, Kurz C, Ferguson LW, Rajput A, Chiu WZ, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Movement disorders: Official Journal of the Movement Disorder Society. 2014;29(14):1758–66.CrossRefGoogle Scholar
  40. 40.
    Lopez G, Bayulkem K, Hallett M. Progressive supranuclear palsy (PSP): Richardson syndrome and other PSP variants. Acta Neurol Scand. 2016;134(4):242–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology. 1992;42(6):1142–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain: a Journal of Neurology. 2002;125(Pt 4):861–70.CrossRefGoogle Scholar
  43. 43.
    Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, et al. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology. 2014;83(5):406–12.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol. 2010;23(4):394–400.PubMedCrossRefGoogle Scholar
  45. 45.
    Respondek G, Roeber S, Kretzschmar H, Troakes C, Al-Sarraj S, Gelpi E, et al. Accuracy of the National Institute for Neurological Disorders and Stroke/Society for Progressive Supranuclear Palsy and Neuroprotection and Natural History in Parkinson Plus Syndromes criteria for the diagnosis of progressive supranuclear palsy. Movement disorders: Official Journal of the Movement Disorder Society. 2013;28(4):504–9.CrossRefGoogle Scholar
  46. 46.
    Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Movement Disorders: Official Journal of the Movement Disorder Society. 2017.Google Scholar
  47. 47.
    Respondek G, Kurz C, Arzberger T, Compta Y, Englund E, Ferguson LW, et al. Which ante mortem clinical features predict progressive supranuclear palsy pathology? Movement disorders: Official Journal of the Movement Disorder Society. 2017.Google Scholar
  48. 48.
    Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A, et al. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun. 2015;6:7247.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lee SE, Rabinovici GD, Mayo MC, Wilson SM, Seeley WW, DeArmond SJ, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol. 2011;70(2):327–40.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Litvan I, Agid Y, Goetz C, Jankovic J, Wenning GK, Brandel JP, et al. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology. 1997;48(1):119–25.PubMedCrossRefGoogle Scholar
  51. 51.
    Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for further study. Journal of Molecular Neuroscience: MN. 2011;45(3):350–3.PubMedCrossRefGoogle Scholar
  52. 52.
    Alexander SK, Rittman T, Xuereb JH, Bak TH, Hodges JR, Rowe JB. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry. 2014;85(8):925–9.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ferrer I, Santpere G, van Leeuwen FW. Argyrophilic grain disease. Brain: a Journal of Neurology. 2008;131(Pt 6):1416–32.CrossRefGoogle Scholar
  54. 54.
    Ahmed Z, Bigio EH, Budka H, Dickson DW, Ferrer I, Ghetti B, et al. Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol. 2013;126(4):537–44.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, et al. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol. 2016;131(1):87–102.PubMedCrossRefGoogle Scholar
  56. 56.
    Whitwell JL, Josephs KA. Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology. Nat Rev Neurol. 2011;8(3):131–42.CrossRefGoogle Scholar
  57. 57.
    McMillan CT, Irwin DJ, Avants BB, Powers J, Cook PA, Toledo JB, et al. White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2013;84(9):949–55.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    McMillan CT, Boyd C, Gross RG, Weinstein J, Firn K, Toledo JB, et al. Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome. Neurology. 2016;87(12):1227–34.PubMedCrossRefGoogle Scholar
  59. 59.
    Kato N, Arai K, Hattori T. Study of the rostral midbrain atrophy in progressive supranuclear palsy. J Neurol Sci. 2003;210(1–2):57–60.PubMedCrossRefGoogle Scholar
  60. 60.
    Adachi M, KAWANAMI T, OHSHIMA H, Sugai Y, Hosoya T. Morning glory sign: a particular MR finding in progressive supranuclear palsy. Magn Reson Med Sci. 2004;3(3):125–32.PubMedCrossRefGoogle Scholar
  61. 61.
    Massey LA, Micallef C, Paviour DC, O'sullivan SS, Ling H, Williams DR, et al. Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. Mov Disord. 2012;27(14):1754–62.PubMedCrossRefGoogle Scholar
  62. 62.
    Massey LA, Micallef C, Paviour DC, O'Sullivan SS, Ling H, Williams DR, et al. Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. Movement Disorders: Official Journal of the Movement Disorder Society. 2012;27(14):1754–62.CrossRefGoogle Scholar
  63. 63.
    Massey LA, Jager HR, Paviour DC, O'Sullivan SS, Ling H, Williams DR, et al. The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy. Neurology. 2013;80(20):1856–61.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Quattrone A, Nicoletti G, Messina D, Fera F, Condino F, Pugliese P, et al. MR imaging index for differentiation of progressive supranuclear palsy from Parkinson disease and the Parkinson variant of multiple system atrophy. Radiology. 2008;246(1):214–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Moller L, Kassubek J, Sudmeyer M, Hilker R, Hattingen E, Egger K, et al. Manual MRI morphometry in Parkinsonian syndromes. Movement Disorders: Official Journal of the Movement Disorder Society. 2017;32(5):778–82.CrossRefGoogle Scholar
  66. 66.
    Nigro S, Arabia G, Antonini A, Weis L, Marcante A, Tessitore A, et al. Magnetic resonance parkinsonism index: diagnostic accuracy of a fully automated algorithm in comparison with the manual measurement in a large Italian multicentre study in patients with progressive supranuclear palsy. Eur Radiol. 2017;27(6):2665–75.PubMedCrossRefGoogle Scholar
  67. 67.
    Zanigni S, Calandra-Buonaura G, Manners DN, Testa C, Gibertoni D, Evangelisti S, et al. Accuracy of MR markers for differentiating progressive supranuclear palsy from Parkinson's disease. NeuroImage Clinical. 2016;11:736–42.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hussl A, Mahlknecht P, Scherfler C, Esterhammer R, Schocke M, Poewe W, et al. Diagnostic accuracy of the magnetic resonance parkinsonism index and the midbrain-to-pontine area ratio to differentiate progressive supranuclear palsy from Parkinson’s disease and the Parkinson variant of multiple system atrophy. Movement Disorders: Official Journal of the Movement Disorder Society. 2010;25(14):2444–9.CrossRefGoogle Scholar
  69. 69.
    Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. Journal of Alzheimer’s Disease: JAD. 2013;34(2):457–68.PubMedGoogle Scholar
  70. 70.
    Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79(6):1094–108.PubMedCrossRefGoogle Scholar
  71. 71.
    Fodero-Tavoletti MT, Okamura N, Furumoto S, Mulligan RS, Connor AR, McLean CA, et al. 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease. Brain: a Journal of Neurology. 2011;134(Pt 4):1089–100.CrossRefGoogle Scholar
  72. 72.
    Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Lowe VJ, Curran G, Fang P, Liesinger AM, Josephs KA, Parisi JE, et al. An autoradiographic evaluation of AV-1451 Tau PET in dementia. Acta Neuropathol Commun. 2016;4(1):58.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Marquie M, Normandin MD, Vanderburg CR, Costantino IM, Bien EA, Rycyna LG, et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015;78(5):787–800.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Cho H, Choi JY, Hwang MS, Lee SH, Ryu YH, Lee MS, et al. Subcortical 18 F-AV-1451 binding patterns in progressive supranuclear palsy. Movement Disorders: Official Journal of the Movement Disorder Society. 2017;32(1):134–40.CrossRefGoogle Scholar
  76. 76.
    Smith R, Schain M, Nilsson C, Strandberg O, Olsson T, Hagerstrom D, et al. Increased basal ganglia binding of 18 F-AV-1451 in patients with progressive supranuclear palsy. Movement Disorders: Official Journal of the Movement Disorder Society. 2017;32(1):108–14.CrossRefGoogle Scholar
  77. 77.
    McMillan CT, Irwin DJ, Nasrallah I, Phillips JS, Spindler M, Rascovsky K, et al. Multimodal evaluation demonstrates in vivo 18F-AV-1451 uptake in autopsy-confirmed corticobasal degeneration. Acta Neuropathol. 2016;132(6):935–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol. 2009;65(4):403–13.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Irwin DJ, McMillan CT, Toledo JB, Arnold SE, Shaw LM, Wang LS, et al. Comparison of cerebrospinal fluid levels of tau and Abeta 1-42 in Alzheimer disease and frontotemporal degeneration using 2 analytical platforms. Arch Neurol. 2012;69(8):1018–25.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Irwin Dea. Ante mortem CSF tau levels correlate with post mortem tau pathology in FTLD. Ann Neurol. 2017; in press. doi: 10.1002/ana.24996.
  81. 81.
    Grossman M, Elman L, McCluskey L, McMillan CT, Boller A, Powers J, et al. Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA neurology. 2014;71(4):442–8.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hu WT, Watts K, Grossman M, Glass J, Lah JJ, Hales C, et al. Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP. Neurology. 2013;in press.Google Scholar
  83. 83.
    Borroni B, Benussi A, Archetti S, Galimberti D, Parnetti L, Nacmias B, et al. Csf p-tau181/tau ratio as biomarker for TDP pathology in frontotemporal dementia. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 2015;16(1–2):86–91.CrossRefGoogle Scholar
  84. 84.
    Borroni B, Malinverno M, Gardoni F, Alberici A, Parnetti L, Premi E, et al. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology. 2008;71(22):1796–803.PubMedCrossRefGoogle Scholar
  85. 85.
    Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI, et al. Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid. Acta Neuropathol. 2017;133(5):751–65.PubMedCrossRefGoogle Scholar
  86. 86.
    Barthelemy NR, Gabelle A, Hirtz C, Fenaille F, Sergeant N, Schraen-Maschke S, et al. Differential mass spectrometry profiles of tau protein in the cerebrospinal fluid of patients with Alzheimer's disease, progressive supranuclear palsy, and dementia with Lewy bodies. Journal of Alzheimer's Disease: JAD. 2016;51(4):1033–43.PubMedCrossRefGoogle Scholar
  87. 87.
    Fabbrini G, Barbanti P, Bonifati V, Colosimo C, Gasparini M, Vanacore N, et al. Donepezil in the treatment of progressive supranuclear palsy. Acta Neurol Scand. 2001;103(2):123–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Lepore V, Defazio G, Acquistapace D, Melpignano C, Pomes L, Lamberti P, et al. Botulinum A toxin for the so-called apraxia of lid opening. Movement Disorders: Official Journal Of the Movement Disorder Society. 1995;10(4):525–6.CrossRefGoogle Scholar
  89. 89.
    Liepelt I, Gaenslen A, Godau J, Di Santo A, Schweitzer KJ, Gasser T, et al. Rivastigmine for the treatment of dementia in patients with progressive supranuclear palsy: clinical observations as a basis for power calculations and safety analysis. Alzheimer’s & Dementia: The Journal of the Alzheimer's Association. 2010;6(1):70–4.CrossRefGoogle Scholar
  90. 90.
    Litvan I, Phipps M, Pharr VL, Hallett M, Grafman J, Salazar A. Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy. Neurology. 2001;57(3):467–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Nieforth KA, Golbe LI. Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol. 1993;16(4):338–46.PubMedCrossRefGoogle Scholar
  92. 92.
    Polo KB, Jabbari B. Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurol. 1994;35(2):237–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Huey ED, Putnam KT, Grafman J. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology. 2006;66(1):17–22.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bensimon G, Ludolph A, Agid Y, Vidailhet M, Payan C, Leigh PN. Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: the NNIPPS study. Brain: a journal of Neurology. 2009;132(Pt 1):156–71.CrossRefGoogle Scholar
  95. 95.
    Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, Eggert KM, et al. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Movement Disorders: Official Journal of the Movement Disorder Society. 2008;23(7):942–9.CrossRefGoogle Scholar
  96. 96.
    Apetauerova D, Scala SA, Hamill RW, Simon DK, Pathak S, Ruthazer R, et al. CoQ10 in progressive supranuclear palsy: a randomized, placebo-controlled, double-blind trial. Neurology(R) neuroimmunology & neuroinflammation. 2016;3(5):e266.CrossRefGoogle Scholar
  97. 97.
    Hampel H, Ewers M, Burger K, Annas P, Mortberg A, Bogstedt A, et al. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. The Journal of Clinical Psychiatry. 2009;70(6):922–31.PubMedCrossRefGoogle Scholar
  98. 98.
    Leclair-Visonneau L, Rouaud T, Debilly B, Durif F, Houeto JL, Kreisler A, et al. Randomized placebo-controlled trial of sodium valproate in progressive supranuclear palsy. Clin Neurol Neurosurg. 2016;146:35–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Hoglinger GU, Huppertz HJ, Wagenpfeil S, Andres MV, Belloch V, Leon T, et al. Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. Movement Disorders: Official Journal of the Movement Disorder Society. 2014;29(4):479–87.CrossRefGoogle Scholar
  100. 100.
    Tolosa E, Litvan I, Hoglinger GU, Burn D, Lees A, Andres MV, et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Movement Disorders: Official Journal of the Movement Disorder Society. 2014;29(4):470–8.CrossRefGoogle Scholar
  101. 101.
    Lovestone S, Boada M, Dubois B, Hull M, Rinne JO, Huppertz HJ, et al. A phase II trial of tideglusib in Alzheimer’s disease. Journal of Alzheimer's Disease: JAD. 2015;45(1):75–88.PubMedGoogle Scholar
  102. 102.
    Cho DH, Lee EJ, Kwon KJ, Shin CY, Song KH, Park JH, et al. Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons. J Neurochem. 2013;126(5):685–95.PubMedCrossRefGoogle Scholar
  103. 103.
    Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2012;32(11):3601–11.CrossRefGoogle Scholar
  104. 104.
    Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. The Lancet Neurology. 2014;13(7):676–85.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Fitzgerald DP, Emerson DL, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, et al. TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther. 2012;11(9):1959–67.PubMedCrossRefGoogle Scholar
  106. 106.
    • Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2007;27(34):9115–29. First preclinical data showing efficacy for active immunization study using tau fragments CrossRefGoogle Scholar
  107. 107.
    Boimel M, Grigoriadis N, Lourbopoulos A, Haber E, Abramsky O, Rosenmann H. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp Neurol. 2010;224(2):472–85.PubMedCrossRefGoogle Scholar
  108. 108.
    Bi M, Ittner A, Ke YD, Gotz J, Ittner LM. Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS One. 2011;6(12):e26860.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Rozenstein-Tsalkovich L, Grigoriadis N, Lourbopoulos A, Nousiopoulou E, Kassis I, Abramsky O, et al. Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. Exp Neurol. 2013;248:451–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Theunis C, Crespo-Biel N, Gafner V, Pihlgren M, Lopez-Deber MP, Reis P, et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau.P301L mice that model tauopathy. PLoS One. 2013;8(8):e72301.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    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. 2014;6(4):44.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Selenica ML, Davtyan H, Housley SB, Blair LJ, Gillies A, Nordhues BA, et al. Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis. J Neuroinflammation. 2014;11:152.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017;16(2):123–34.PubMedCrossRefGoogle Scholar
  114. 114.
    • Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011;118(4):658–67. First report of preclinical data for passive tau immunotherapy in murine model of tauopathy PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, et al. Passive immunization with anti-tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J Biol Chem. 2011;286(39):34457–67.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Collin L, Bohrmann B, Göpfert U, Oroszlan-Szovik K, Ozmen L, Grüninger F. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer‘s disease. Brain : a journal of neurology. 2014;137(10):2834–46.CrossRefGoogle Scholar
  117. 117.
    Walls KC, Ager RR, Vasilevko V, Cheng D, Medeiros R, LaFerla FM. p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice. Neurosci Lett. 2014;575:96–100.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Kiritoshi T, Neugebauer V, et al. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep. 2012;2:700.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Muñoz MJ, Lasagna-Reeves CA, Kayed R. Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis. 2014;40(s1):S97–S111.PubMedCrossRefGoogle Scholar
  120. 120.
    Ittner A, Bertz J, Suh LS, Stevens CH, Gotz J, Ittner LM. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J Neurochem. 2015;132(1):135–45.PubMedCrossRefGoogle Scholar
  121. 121.
    Sankaranarayanan S, Barten DM, Vana L, Devidze N, Yang L, Cadelina G, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One. 2015;10(5):e0125614.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80(2):402–14.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Annals of Clinical and Translational Neurology. 2015;2(3):278–88.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    • Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid ß-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316(5825):750–4. Novel data suggesting reducing tau expression could be a therapeutic strategy for AD PubMedCrossRefGoogle Scholar
  125. 125.
    Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell. 2010;142(3):387–97.PubMedCrossRefGoogle Scholar
  126. 126.
    Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, 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. 2011;31(2):700–11.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M, et al. Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice. Am J Pathol. 2012;181(6):1928–40.PubMedCrossRefGoogle Scholar
  128. 128.
    Peacey E, Rodriguez L, Liu Y, Wolfe MS. Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing. Nucleic acids res. 2012:gks710.Google Scholar
  129. 129.
    Piedrahita D, Hernandez I, Lopez-Tobon A, Fedorov D, Obara B, Manjunath BS, et al. Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer's mice. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2010;30(42):13966–76.CrossRefGoogle Scholar
  130. 130.
    Xu H, Rosler TW, Carlsson T, de Andrade A, Fiala O, Hollerhage M, et al. Tau silencing by siRNA in the P301S mouse model of tauopathy. Current Gene Therapy. 2014;14(5):343–51.PubMedCrossRefGoogle Scholar
  131. 131.
    Matsuo ES, Shin RW, Billingsley ML, Van de Voorde A, O'Connor M, Trojanowski JQ, 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. 1994;13(4):989–1002.PubMedCrossRefGoogle Scholar
  132. 132.
    Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33(1):95–130.PubMedCrossRefGoogle Scholar
  133. 133.
    Ferrer I, Barrachina M, Puig B. Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol. 2002;104(6):583–91.PubMedGoogle Scholar
  134. 134.
    Patrick GN, Zukerberg L, Nikolic M, de La Monte S, Dikkes P, Tsai L-H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999;402(6762):615–22.PubMedCrossRefGoogle Scholar
  135. 135.
    Long ZM, Zhao L, Jiang R, Wang KJ, Luo SF, Zheng M, et al. Valproic acid modifies synaptic structure and accelerates Neurite outgrowth via the glycogen synthase kinase-3beta signaling pathway in an Alzheimer’s disease model. CNS Neuroscience & Therapeutics. 2015;21(11):887–97.CrossRefGoogle Scholar
  136. 136.
    Xuan AG, Pan XB, Wei P, Ji WD, Zhang WJ, Liu JH, et al. Valproic acid alleviates memory deficits and attenuates amyloid-beta deposition in transgenic mouse model of Alzheimer’s disease. Mol Neurobiol. 2015;51(1):300–12.PubMedCrossRefGoogle Scholar
  137. 137.
    Nakashima H, Ishihara T, Suguimoto P, Yokota O, Oshima E, Kugo A, et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 2005;110(6):547–56.PubMedCrossRefGoogle Scholar
  138. 138.
    Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005;102(19):6990–5.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Sundaram JR, Poore CP, Sulaimee NH, Pareek T, Asad AB, Rajkumar R, et al. Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2013;33(1):334–43.CrossRefGoogle Scholar
  140. 140.
    Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012;8(4):393–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Wang AC, Jensen EH, Rexach JE, Vinters HV, Hsieh-Wilson LC. Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration. Proc Natl Acad Sci U S A. 2016;113(52):15120–5.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67(6):953–66.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:252.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Bachanova V, Burns LJ, Ahn KW, Laport GG, Akpek G, Kharfan-Dabaja MA, et al. Impact of pretransplantation (18)F-fluorodeoxy glucose-positron emission tomography status on outcomes after allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2015;21(9):1605–11.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A. 1996;93(20):11213–8.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Arai T, Hasegawa M, Nonoka T, Kametani F, Yamashita M, Hosokawa M, et al. Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology: Official Journal of the Japanese Society of Neuropathology. 2010;30(2):170–81.CrossRefGoogle Scholar
  147. 147.
    Crowe A, James MJ, Lee VM, Smith AB 3rd, Trojanowski JQ, Ballatore C, et al. Aminothienopyridazines and methylene blue affect tau fibrillization via cysteine oxidation. J Biol Chem. 2013;288(16):11024–37.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    • Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, 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 U S A. 2005;102(1):227–31. Detailed preclinical study of microtubule stabalizing agents in murin model of tauopathy PubMedCrossRefGoogle Scholar
  149. 149.
    Magen I, Ostritsky R, Richter F, Zhu C, Fleming SM, Lemesre V, et al. Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing alpha-synuclein. Pharmacol Res Perspect. 2014;2(5):e00065.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Barten DM, Fanara P, Andorfer C, Hoque N, Wong PY, Husted KH, et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2012;32(21):7137–45.CrossRefGoogle Scholar
  151. 151.
    Brunden KR, Gardner NM, James MJ, Yao Y, Trojanowski JQ, Lee VM, et al. MT-stabilizer, dictyostatin, exhibits prolonged brain retention and activity: potential therapeutic implications. ACS Med Chem Lett. 2013;4(9):886–9.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    • Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of tau aggregation by fibrillar species. J Biol Chem. 2012;287(23):19440–51. Novel data demonstrating propogation of tau aggregations between cells which is blocked by tau-specific antibodies PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Rosenmann H, Grigoriadis N, Karussis D, Boimel M, Touloumi O, Ovadia H, et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol. 2006;63(10):1459–67.PubMedCrossRefGoogle Scholar
  154. 154.
    • Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med. 2015;21(6):394–402. Comprehensive review of epitopes studied for tau directed passive immunotherapies PubMedCrossRefGoogle Scholar
  155. 155.
    Igawa T, Tsunoda H, Kuramochi T, Sampei Z, Ishii S, Hattori K. Engineering the variable region of therapeutic IgG antibodies. MAbs. 2011;3(3):243–52.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Sigurdsson EM. Tau immunotherapy. Neurodegener Dis. 2016;16(1–2):34–8.PubMedCrossRefGoogle Scholar
  157. 157.
    Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP. Inhibition of neuronal maturation in primary hippocampal neurons from τ deficient mice. J Cell Sci. 2001;114(6):1179–87.PubMedGoogle Scholar
  158. 158.
    Morris M, Hamto P, Adame A, Devidze N, Masliah E, Mucke L. Age-appropriate cognition and subtle dopamine-independent motor deficits in aged tau knockout mice. Neurobiol Aging. 2013;34(6):1523–9.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Lei P, Ayton S, Moon S, Zhang Q, Volitakis I, Finkelstein DI, et al. Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol Neurodegener. 2014;9:29.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Ahmed T, Van der Jeugd A, Blum D, Galas M-C, D’Hooge R, Buee L, et al. Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion. Neurobiol Aging. 2014;35(11):2474–8.PubMedCrossRefGoogle Scholar
  161. 161.
    Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012;18(2):291–5.PubMedCrossRefGoogle Scholar
  162. 162.
    Santa-Maria I, Alaniz ME, Renwick N, Cela C, Fulga TA, Van Vactor D, et al. Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest. 2015;125(2):681–6.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    DeVos SL, Miller TM. Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics. 2013;10(3):486–97.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Sud R, Geller ET, Schellenberg GD. Antisense-mediated exon skipping decreases tau protein expression: a potential therapy for tauopathies. Molecular Therapy-Nucleic Acids. 2014;3:e180.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, et al. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest. 2006;116(8):2290–6.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. The Lancet Neurology. 2013;12(5):435–42.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, et al. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron. 2012;74(6):1031–44.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet (London, England). 2016;388(10063):3017–26.CrossRefGoogle Scholar
  169. 169.
    DeVos SL, Miller TM. Direct intraventricular delivery of drugs to the rodent central nervous system. JoVE (Journal of Visualized Experiments). 2013(75):e50326-e.Google Scholar
  170. 170.
    Gomes MJ, Dreier J, Brewer J, Martins S, Brandl M, Sarmento B. A new approach for a blood-brain barrier model based on phospholipid vesicles: membrane development and siRNA-loaded nanoparticles permeability. J Membr Sci. 2016;503:8–15.CrossRefGoogle Scholar
  171. 171.
    Shen H, Sun T, Ferrari M. Nanovector delivery of siRNA for cancer therapy. Cancer Gene Ther. 2012;19(6):367–73.PubMedCrossRefGoogle Scholar
  172. 172.
    Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood–brain barrier by nanoparticles. J Control Release. 2012;161(2):264–73.PubMedCrossRefGoogle Scholar
  173. 173.
    Morris K, Rossi J. Lentiviral-mediated delivery of siRNAs for antiviral therapy. Gene Ther. 2006;13(6):553–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D. AAV vector–mediated RNAi of mutant Huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease. Mol Ther. 2008;16(5):947–56.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Raoul C, Abbas-Terki T, Bensadoun J-C, Guillot S, Haase G, Szulc J, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med. 2005;11(4):423–8.PubMedCrossRefGoogle Scholar
  176. 176.
    Ceccarelli I, Fiengo P, Remelli R, Miragliotta V, Rossini L, Biotti I, et al. Recombinant adeno associated viral (AAV) vector type 9 delivery of Ex1-Q138-mutant Huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery. Neurobiol Dis. 2016;86:41–51.PubMedCrossRefGoogle Scholar
  177. 177.
    Grondin R, Kaytor MD, Ai Y, Nelson PT, Thakker DR, Heisel J, et al. Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain: a Journal of Neurology. 2012;135(Pt 4):1197–209.CrossRefGoogle Scholar
  178. 178.
    Alecou T, Giannakou M, Damianou C. Amyloid-beta plaque reduction with antibodies crossing the blood-brain barrier, which was opened in 3 sessions of focused ultrasound in a rabbit model. Journal of Ultrasound in Medicine: Official Journal of the American Institute of Ultrasound in Medicine. 2017.Google Scholar
  179. 179.
    Mead BP, Kim N, Miller GW, Hodges D, Mastorakos P, Klibanov AL, et al. Novel focused ultrasound gene therapy approach noninvasively restores dopaminergic neuron function in a rat Parkinson’s disease model. Nano Lett. 2017.Google Scholar
  180. 180.
    Yin Y, Cao L, Ge H, Duanmu W, Tan L, Yuan J, et al. L-Borneol induces transient opening of the blood-brain barrier and enhances the therapeutic effect of cisplatin. Neuroreport. 2017;28(9):506–13.PubMedCrossRefGoogle Scholar
  181. 181.
    Vazana U, Veksler R, Pell GS, Prager O, Fassler M, Chassidim Y, et al. Glutamate-mediated blood-brain barrier opening: implications for neuroprotection and drug delivery. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2016;36(29):7727–39.CrossRefGoogle Scholar
  182. 182.
    Gao X, Qian J, Zheng S, Changyi Y, Zhang J, Ju S, et al. Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist. ACS Nano. 2014;8(4):3678–89.PubMedCrossRefGoogle Scholar
  183. 183.
    Rohrer JD, Nicholas JM, Cash DM, van Swieten J, Dopper E, Jiskoot L, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015;14(3):253–62.PubMedCrossRefGoogle Scholar
  184. 184.
    Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, et al. Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris Water Maze with aging. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience. 2014;34(21):7124–36.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Frontotemporal Dementia Center (FTDC)University of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  2. 2.University of Pennsylvania Perelman School of Medicine, Hospital of the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations