Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer's Disease

Developing Therapeutics for Alzheimer's Disease: Progress and Challenges

Volumn , Issue , 2016, Pages 385-436

  Wischik, C M ^a,b   Storey, J M D ^a,b   Wischik, D J ^a,b   Harrington, C R ^a  

^a UNIVERSITY OF ABERDEEN   (United Kingdom)

^b TAURX THERAPEUTICS LTD   (United Kingdom)

Author keywords

Alzheimer's disease; Clinical trials; LMTX; Methylthioninium; Tau aggregation inhibitors; Tau protein; Tauopathy

Indexed keywords

EID: 85011914751     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-802173-6.00015-0     Document Type: Chapter

References (171)

1. Abraha A., Ghoshal N., Gamblin T.C., Cryns V., Berry R.W., Kuret J., Binder L.I. C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. J Cell Sci 2000, 113:3737-3745.
2. Akoury E., Pickhardt M., Gajda M., Biernat J., Mandelkow E., Zweckstetter M. Mechanistic basis of phenothiazine-driven inhibition of tau aggregation. Angew Chem Int Ed 2013, 52:3511-3515.
3. Allen B., Ingram E., Takao M., Smith M.J., Jakes R., Virdee K., Yoshida H., Holzer M., Craxton M., Emson P.C., Atzori C., Migheli A., Crowther R.A., Ghetti B., Spillantini M.G., Goedert M. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002, 22:9340-9351.
4. Alonso A.D., Zaidi T., Grundke-Iqbal I., Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer's disease. Proc Natl Acad Sci USA 1994, 91:5562-5566.
5. Alzheimer A. über eine eigenartige Erkrankung der Hirnrinde. Allg Z Psych Psych-Gerich Med 1907, 64:146-148.
6. Anderton B.H., Breinburg D., Downes M.J., Green P.J., Tomlinson B.E., Ulrich J., Wood J.N., Kahn J. Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature 1982, 298:84-86.
7. Aoyagi H., Hasegawa M., Tamaoka A. Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau, but not wild-type tau. J Biol Chem 2007, 282:20309-20318.
8. Arendt T., Stieler J., Strijkstra A.M., Hut R.A., Rudiger J., Van der Zee E.A., Harkany T., Holzer M., Hartig W. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 2003, 23:6972-6981.
9. Arrasate M., Pérez M., Valpuesta J.M., Avila J. Role of glycosaminoglycans in determining the helicity of paired helical filaments. Am J Pathol 1997, 151:1115-1122.
10. Arriagada P.W., Growdon J.H., Hedley-White E.T., Hyman B.T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 1992, 42:631-639.
11. Baddeley T.C., McCaffrey J., Storey J.M.D., Cheung J.K.S., Melis V., Horsley D., Harrington C.R., Wischik C.M. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Therap 2015, 352:110-118.
12. Bancher C., Braak H., Fischer P., Jellinger K. Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease. Neurosci Lett 1993, 162:179-182.
13. Bancher C., Jellinger K., Lassmann H., Fischer P., Leblhuber F. Correlations between mental state and quantitative neuropathology in the Vienna Longitudinal Study on Dementia. Eur Arch Psychiatry Clin Neurosci 1996, 246:137-146.
14. Bateman R.J., Xiong C., Benzinger T.L.S., Fagan A.M., Goate A., Fox N.C., Marcus D.S., Cairns N.J., Xie X., Blazey T.M., Holtzman D.M., Santacruz A., Buckles V., Oliver A., Moulder K., Aisen P.S., Ghetti B., Klunk W.E., McDade E., Martins R.N., Masters C.L., Mayeux R., Ringman J.M., Rossor M.N., Schofield P.R., Sperling R.A., Salloway S., Morris J.C. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. New Eng J Med 2012, 367:795-804.
15. Berry R.W., Abraha A., Lagalwar S., LaPointe N., Gamblin T.C., Cryns V.L., Binder L.I. Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. Biochemistry 2003, 42:8325-8331.
16. Biernat J., Gustke N., Drewes G., Mandelkow E-M., Mandelkow E. Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 1993, 11:153-163.
17. Blocq P., Marinesco G. Sur les lésions et la pathogénie de l'épilepsie des dite essentielle. Sem Méd 1892, 12:445-446.
18. Bondareff W., Wischik C.M., Novak M., Roth M. Sequestration of tau by granulovacuolar degeneration in Alzheimer's disease. Am J Pathol 1991, 139:641-647.
19. Bondareff W., Harrington C., Wischik C.M., Hauser D.L., Roth M. Immunohistochemical staging of neurofibrillary degeneration in Alzheimer's disease. J Neuropathol Exptl Neurol 1994, 53:158-164.
20. Boyce W.H., McKinney W.M., Long T.T., Drach G.W. Oral administration of methylene blue to patients with renal calculi. J Urol 1967, 97:783-789.
21. Braak H., Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991, 82:239-259.
22. Braak H., Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol 2011, 121:171-181.
23. Braak H., Zetterberg H., Del Tredici K., Blennow K. Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-beta changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol 2013, 126:631-641.
24. Bradley K.M., O'Sullivan V.T., Soper N.D.W., Nagy Z., King E.M.-F., Smith A.D., Shepstone B.J. Cerebral perfusion SPET correlated with Braak pathological stage in Alzheimer's disease. Brain 2002, 125:1772-1781.
25. Brion J-P., Passareiro H., Nunez J., Flament-Durand J. Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d'Alzheimer. Arch Biol (Brux) 1985, 95:229-235.
26. Buchhave P., Minthon L., Zetterberg H., Wallin Å., Blennow K., Hansson O. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiat 2012, 69:98-106.
27. Bulic B., Pickhardt M., Schmidt B., Mandelkow E.M., Waldmann H., Mandelkow E. Development of tau aggregation inhibitors for Alzheimer's disease. Angew Chem Int Ed 2009, 48:1740-1752.
28. Chakrabarty P., Hudson V.J., Sacino A.N., Brooks M.M., D'Alton S., Lewis J., Golde T.E., Giasson B.I. Inefficient induction and spread of seeded tau pathology in P301L mouse model of tauopathy suggests inherent physiological barriers to transmission. Acta Neuropathol 2015, 303-305.
29. Chien D.T., Bahri S., Szardenings A.K., Walsh J.C., Mu F., Su M.-Y., Shankle W.R., Elizarov A., Kolb H.C. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis 2013, 34:457-468.
30. Chies A.B., Custódio R.C., de Souza G.L., Corrêa F.M., Pereira O.C. Pharmacological evidence that methylene blue inhibits noradrenaline neuronal uptake in the rat vas deferens. Pol J Pharmacol 2003, 55:573-579.
31. Chirita C., Necula M., Kuret J. Ligand-dependent inhibition and reversal of tau filament formation. Biochemistry 2004, 43:2879-2887.
32. Choi S.H., Kim Y.H., Hebisch M., Sliwinski C., Lee S., D'Avanzo C., Chen H., Hooli B., Asselin C., Muffat J., Klee J.B., Zhang C., Wainger B.J., Peitz M., Kovacs D.M., Woolf C.J., Wagner S.L., Tanzi R.E., Kim D.Y. A three-dimensional human neural cell culture model of Alzheimer's disease. Nature 2014, 515:274-278.
33. Clavaguera F., Bolmont T., Crowther R.A., Abramowski D., Frank S., Probst A., Fraser G., Stalder A.K., Beibel M., Staufenbiel M., Jucker M., Goedert M., Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nature Cell Biol 2009, 11:909-914.
34. Clavaguera F., Lavenir I., Falcon B., Frank S., Goedert M., Tolnay M. Prion-like templated misfolding in tauopathies. Brain Pathol 2013, 23:342-349.
35. Congdon E.E., Wu J.W., Myeku N., Figueroa Y.H., Herman M., Marinec P.S., Gestwicki J.E., Dickey C.A., Yu W.H., Duff K.E. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 2012, 8:609-622.
36. Crowe A., Ballatore C., Hyde E., Trojanowski J.Q., Lee V.M.Y. High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation. Biochem Biophys Res Commun 2007, 358:1-6.
37. Crowe A., Huang W., Ballatore C., Johnson R.L., Hogan A.-M.L., Huang R., Wichtermann J., McCoy J., Huryn D.M., Auld D.S., Smith A.B., Inglese J., Trojanowski J.Q., Austin C.P., Brunden K.R., Lee V.M.Y. The identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 2009, 48:7732-7745.
38. Crowther R.A., Olesen O.F., Jakes R., Goedert M. The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer's disease. FEBS Lett 1992, 309:199-202.
39. Denk F., Wade-Martins R. Knock-out and transgenic mouse models of tauopathies. Neurobiol Aging 2009, 30:1-13.
40. Deutsch S.I., Rosse R.B., Paul S.M., Tomasino V., Koetzner L., Morn C.B., Mastropaolo J. 7-Nitroindazole and methylene blue, inhibitors of neuronal nitric oxide synthase and NO-stimulated guanylate cyclase, block MK-801-elicited behaviors in mice. Neuropsychopharmacology 1996, 15:37-43.
41. Dickey C., Ash P., Klosak N., Lee W., Petrucelli L., Hutton M., Eckman C. Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener 2006, 1:6.
42. Donohue M.C., Jacqmin-Gadda H., Le Goff M., Thomas R.G., Raman R., Gamst A.C., Beckett L.A., Jack C.R., Weiner M.W., Dartigues J.-F., Aisen P.S. Estimating long-term multivariate progression from short-term data. Alzheimers Dement 2014, 10:S400-S410.
43. Doody R.S., Thomas R.G., Farlow M., Iwatsubo T., Vellas B., Joffe S., Kieburtz K., Raman R., Sun X., Aisen P.S., Siemers E., Liu-Seifert H., Mohs R. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. New Eng J Med 2014, 370:311-321.
44. Duyckaerts C. Tau pathology in children and young adults: can you still be unconditionally baptist?. Acta Neuropathol 2011, 121:145-147.
45. Duyckaerts C., Bennecib M., Grignon Y., Uchihara T., He Y., Piette F., Hauw J-J. Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol Aging 1997, 18:267-273.
46. Fasulo L., Ovecka M., Kabát J., Bradbury A., Novák M., Cattaneo A. Overexpression of Alzheimer's PHF core tau fragments: implications for the tau truncation hypothesis. Alzheimers Res 1996, 2:195-200.
47. Fasulo L., Ugolini G., Cattaneo A. Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K. J Alzheimers Dis 2005, 7:3-13.
48. Fasulo L., Ugolini G., Visintin M., Bradbury A., Brancolini C., Verzillo V., Novak M., Cattaneo A. The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J Neurochem 2000, 75:624-633.
49. Fasulo L., Visintin M., Novak M., Cattaneo A. Tau truncation in Alzheimer's disease: expression of a fragment encompassing PHF core tau induces apoptosis in COS cells. Alzheimers Rep 1998, 1:25-32.
50. Filipcik P., Cente M., Krajciova G., Vanicky I., Novak M. Cortical and hippocampal neurons from truncated tau transgenic rat express multiple markers of neurodegeneration. Cell Mol Neurobiol 2009, 29:895-900.
51. Fischer O. Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschr Psychiat Neurol 1907, 22:361-372.
52. Flores-Rodríguez P., Ontiveros-Torres M.A., Cárdenas-Aguayo M.C., Luna-Arias J.P., Meraz-Rios M.A., Viramontes-Pintos A., Harrington C.R., Wischik C.M., Mena R., Florán-Garduño B., Luna-Muñoz J. The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease. Frontiers Neurosci 2015, 9:33.
53. Friedhoff P., von Bergen M., Mandelkow E.-M., Davies P., Mandelkow E. A nucleated assembly of Alzheimer paired helical filaments. Proc Natl Acad Sci USA 1998, 95:15712-15717.
54. Frost B., Jacks R.L., Diamond M.I. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009, 284:12845-12852.
55. Frost B., Diamond M.I. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 2010, 11:155-159.
56. Gamblin T.C., Chen F., Zambrano A., Abraha A., Lagalwar S., Guillozet A.L., Lu M., Fu Y., Garcia-Sierra F., LaPointe N., Miller R., Berry R.W., Binder L.I., Cryns V.L. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA 2003, 100:10032-10037.
57. García-Sierra F., Wischik C.M., Harrington C.R., Luna-Muñoz J., Mena R. Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's disease. J Chem Neuroanat 2001, 22:65-77.
58. Gertz H-J., Xuereb J.H., Huppert F.A., Brayne C., Kuüger H., McGee M.A., Paykel E.S., Harrington C.R., Mukaetova-Ladinska E.B., O'Connor D.W., Wischik C.M. The relationship between clinical dementia and neuropathological staging (Braak) in a very elderly community sample. Eur Arch Psychiatry Clin Neurosci 1996, 246:132-136.
59. Goedert M., Clavaguera F., Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 2010, 33:317-325.
60. Goedert M., Jakes R., Spillantini M.G., Hasegawa M., Smith M.J., Crowther R.A. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 1996, 383:550-553.
61. Goedert M., Spillantini M.G., Cairns N.J., Crowther R.A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992, 8:159-168.
62. Grober E., Dickson D., Sliwinski M.J., Buschke H., Katz M., Crystal H., Lipton R.B. Memory and mental status correlates of modified Braak staging. Neurobiol Aging 1999, 20:573-579.
63. Grundke-Iqbal I., Iqbal K., Quinlan M., Tung Y-C., Zaida M.S., Wisniewski H.M. Microtubule associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 1986, 261:6084-6089.
64. Grundke-Iqbal I., Iqbal K., Tung Y.C., Quinlan M., Wisniewski H.M., Binder L.I. Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986, 83:4913-4917.
65. Guillozet-Bongaarts A.L., Cahill M.E., Cryns V.L., Reynolds M.R., Berry R.W., Binder L.I. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem 2006, 97:1005-1014.
66. Guillozet-Bongaarts A.L., Garcia-Sierra F., Reynolds M.R., Horowitz P.M., Fu Y., Wang T., Cahill M.E., Bigio E.H., Berry R.W., Binder L.I. Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease. Neurobiol Aging 2005, 26:1015-1022.
67. Guo J.L., Lee V.M.Y. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 2011, 286:15317-15331.
68. Hall A.M., Roberson E.D. Mouse models of Alzheimer's disease. Brain Res Bull 2012, 88:3-12.
69. Hall G., Lee S., Yao J. Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by application of a compound which inhibits tau filament formation in vitro. J Mol Neurosci 2002, 19:251-260.
70. Hardy J., Allsop D. Amyloid depositions as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991, 12:383-388.
71. Harrington C.R., Mukaetova-Ladinska E.B., Hills R., Edwards P.C., Montejo De Garcini E., Novak M., Wischik C.M. Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease. Proc Natl Acad Sci USA 1991, 88:5842-5846.
72. Harrington C.R., Storey J.M.D., Clunas S., Harrington K.A., Horsley D., Ishaq A., Kemp S.J., Larch C.P., Marshall C., Nicoll S.L., Rickard J.E., Simpson M., Sinclair J.P., Storey L.J., Wischik C.M. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer's disease. J Biol Chem 2015, 290:10862-10875.
73. Hasegawa M., Crowther R.A., Jakes R., Goedert M. Alzheimer-like changes in microtubule-associated protein tau induced by sulfated glycosaminoglycans: inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. J Biol Chem 1997, 272:33118-33124.
74. Hebert L.E., Weuve J., Scherr P.A., Evans D.A. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013, 80:1778-1783.
75. Herholz K., Schopphoff H., Schmidt M., Mielke R., Eschner W., Scheidhauer K., Schicha H., Heiss W-D., Ebmeier K. Direct comparison of spatially normalized PET and SPECT scans in Alzheimer's disease. J Nuc Med 2002, 43:21-26.
76. Holmes B.B., Furman J.L., Mahan T.E., Yamasaki T.R., Mirbaha H., Eades W.C., Belaygorod L., Cairns N.J., Holtzman D.M., Diamond M.I. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA 2014, 111:E4376-E4385.
77. Honson N.S., Jensen J.R., Darby M.V., Kuret J. Potent inhibition of tau fibrillization with a multivalent ligand. Biochem Biophys Res Commun 2007, 363:229-234.
78. Hosokawa M., Arai T., Masuda-Suzukake M., Nonaka T., Yamashita M., Akiyama H., Hasegawa M. Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. PLoS One 2012, 7:e52389.
79. Hrnkova M., Zilka N., Minichova Z., Koson P., Novak M. Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res 2007, 1130:206-213.
80. Hurtado D.E., Molina-Porcel L., Iba M., Aboagye A.K., Paul S.M., Trojanowski J.Q., Lee V.M.-Y. Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model. Am J Pathol 2010, 177:1977-1988.
81. Huvent I., Kamah A., Cantrelle F-X., Barois N., Slomianny C., Smet-Nocca C., Landrieu I., Lippens G. A functional fragment of tau forms fibers without the need for an intermolecular cysteine bridge. Biochem Biophys Res Commun 2014, 445:299-303.
82. Ihara Y., Morishima-Kawashima M., Nixon R. The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harb Perspect Med 2012, 2.
83. Ihara Y., Nukina N., Miura R., Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem 1986, 99:1807-1810.
84. Iqbal K., Liu F., Gong C-X. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol 2014, 88:631-639.
85. Irwin D.J., Cairns N.J., Grossman M., McMillan C.T., Lee E.B., Van Deerlin V.M., Lee V.M.-Y., Trojanowski J.Q. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol 2015, 129:469-491.
86. Jack C.R., Knopman D.S., Jagust W.J., Petersen R.C., Weiner M.W., Aisen P.S., Shaw L.M., Vemuri P., Wiste H.J., Weigand S.D., Lesnick T.G., Pankratz V.S., Donohue M.C., Trojanowski J.Q. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 2013, 12:207-216.
87. Jack C.R.J., Vemuri P., Wiste H.J., Weigand S.D., Lesnick T.G., Lowe V., Kantarci K., Bernstein M.A., Senjem M.L., Gunter J.L., Boeve B.F., Trojanowski J.Q., Shaw L.M., Aisen P.S., Weiner M.W., Petersen R.C., Knopman D.S. Shapes of the trajectories of 5 major biomarkers of Alzheimer disease. Arch Neurol 2012, 69:856-867. Alzheimer's Disease Neuroimaging Initiative.
88. Jakes R., Novak M., Davison M., Wischik C.M. Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer's disease. EMBO J 1991, 10:2725-2729.
89. Jinwal U.K., Miyata Y., Koren J., Jones J.R., Trotter J.H., Chang L., O'Leary J., Morgan D., Lee D.C., Shults C.L., Rousaki A., Weeber E.J., Zuiderweg E.R.P., Gestwicki J.E., Dickey C.A. Chemical manipulation of Hsp70 ATPase activity regulates tau stability. J Neurosci 2009, 29:12079-12088.
90. Jobst K.A., Smith A.D., Barker C.S., Wear A., King E.M., Smith A., Anslow P.A., Molyneux A.J., Shepstone B.J., Soper N., Holmes K.A., Robinson J.R., Hope R.A., Oppenheimer C., Brockbank K., McDonald B. Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer's disease. J Neurol Neurosurg Psychiat 1992, 55:190-194.
91. Kampers T., Friedhoff P., Biernat J., Mandelkow E-M., Mandelkow E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett 1996, 399:344-349.
92. Kidd M. Paired helical filaments in electron microscopy in Alzheimer's disease. Nature 1963, 197:192-193.
93. Koson P., Zilka N., Kovac A., Kovacech B., Korenova M., Filipcik P., Novak M. Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci 2008, 28:239-246.
94. Lai R.Y.K., Gertz H.-J., Wischik D.J., Xuereb J.H., Mukaetova-Ladinska E.B., Harrington C.R., Edwards P.C., Mena R., Paykel E.S., Brayne C., Huppert F.A., Roth M., Wischik C.M. Examination of phosphorylated tau protein as a PHF-precursor at early stage Alzheimer's disease. Neurobiol Aging 1995, 16:433-445.
95. Lai R.Y.K., Harrington C.R., Wischik C.M. Absence of a role for phosphorylation in the tau pathology of Alzheimer's disease. Biomolecules 2016, 6:19.
96. Lee V.M.-Y., Balin B.J., Otvos L.J., Trojanowski J.Q. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991, 251:675-678.
97. Li W., Sperry J.B., Crowe A., Trojanowski J.Q., Smith A.B., Lee V.M.Y. Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 2009, 110:1339-1351.
98. Luna-Munoz J., Chavez-Macias L., Garcia-Sierra F., Mena R. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. J Alzheimer's Dis 2007, 12:365-375.
99. Mansouri A., Lurie A.A. Concise review: methemoglobinemia. Am J Hematol 1993, 42:7-12.
100. Maruyama M., Shimada H., Suhara T., Shinotoh H., Ji B., Maeda J., Zhang M-R., Trojanowski J.Q., Lee V.M.Y., Ono M., Masamoto K., Takano H., Sahara N., Iwata N., Okamura N., Furumoto S., Kudo Y., Chang Q., Saido T.C., Takashima A., Lewis J., Jang M.-K., Aoki I., Ito H., Higuchi M. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013, 79:1094-1108.
101. Masters C., Simms G., Weinman N., Multhaup G., McDonald B., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985, 82:4245-4249.
102. Masters C.L., Multhaup G., Simms G., Pottgiesser J., Martins R.N., Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 1985, 4:2757-2763.
103. Matsuda H. Role of neuroimaging in Alzheimer's disease, with emphasis on brain perfusion SPECT. J Nuc Med 2007, 48:1289-1300.
104. May J.M., Qu Z.-C., Cobb C.E. Reduction and uptake of methylene blue by human erythrocytes. Am J Physiol-Cell Physiol 2004, 286:C1390-C1398.
105. Mayer B., Brunner F., Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 1993, 45:367-374.
106. Medina D.X., Caccamo A., Oddo S. Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 2011, 21:140-149.
107. Melis V., Magbagbeolu M., Rickard J.E., Horsley D., Davidson K., Harrington K.A., Goatman K., Goatman E.A., Deiana S., Close S.P., Zabke C., Stamer K., Dietze S., Schwab K., Storey J.M.D., Harrington C.R., Wischik C.M., Theuring F., Riedel G. Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol 2015, 26:353-368.
108. Melis V., Zabke C., Stamer K., Magbagbeolu M., Schwab K., Marschall P., Veh R.W., Bachmann S., Deiana S., Moreau P.H., Davidson K., Harrington K.A., Rickard J.E., Horsley D., Garman R., Mazurkiewicz M., Niewiadomska G., Wischik C.M., Harrington C.R., Riedel G., Theuring F. Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration. Cell Mol Life Sci 2015, 72:2199-2222.
109. Mena R., Edwards P.C., Harrington C.R., Mukaetova-Ladinska E.B., Wischik C.M. Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer's disease. Acta Neuropathol 1996, 91:633-641.
110. Mena R., Edwards P., Pérez-Olvera O., Wischik C.M. Monitoring pathological assembly of tau and β-amyloid proteins in Alzheimer's disease. Acta Neuropathol 1995, 89:50-56.
111. Mori H., Kondo J., Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 1987, 235:1641-1644.
112. Mosconi L., Mistur R., Switalski R., Tsui W.H., Glodzik L., Li Y., Pirraglia E., De Santi S., Reisberg B., Wisniewski T., de Leon M.J. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur J Nuc Med Mol Imaging 2009, 36:811-822.
113. Mukaetova-Ladinska E.B., Garcia-Sierra F., Hurt J., Gertz H.J., Xuereb J.H., Hills R., Brayne C., Huppert F.A., Paykel E.S., McGee M., Jakes R., Honer W.G., Harrington C.R., Wischik C.M. Staging of cytoskeletal and β-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease. Am J Pathol 2000, 157:623-636.
114. 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum. Brain 2015, 1370-1381.
115. Murthy A.S.N., Reddy K.S. Cyclic-voltammetric studies of some phenothiazine dyes. J Chem Soc Faraday Trans 1 Phys Chem Condensed Phases 1984, 80:2745-2750.
116. Naylor G.J., Martin B., Hopwood S.E., Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry 1986, 21:915-920.
117. Neary D., Snowden J.S., Gustafson L., Passant U., Stuss D., Black S., Freedman M., Kertesz A., Robert P.H., Albert M., Boone K., Miller B.L., Cummings J., Benson D.F. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998, 51:1546-1554.
118. Necula M., Breydo L., Milton S., Kayed R., van der Veer W.E., Tone P., Glabe C.G. Methylene blue inhibits amyloid Aβ oligomerization by promoting fibrillization. Biochemistry 2007, 46:8850-8860.
119. Necula M., Kayed R., Milton S., Glabe C.G. Small-molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 2007, 282:10311-10324.
120. Novak M., Jakes R., Edwards P.C., Milstein C., Wischik C.M. Difference between the tau protein of Alzheimer paired helical filament core and normal tau revealed by epitope analysis of mAbs 423 and 7.51. Proc Natl Acad Sci USA 1991, 88:5837-5841.
121. 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 1993, 12:365-370.
122. Ohm T.G., Müller H., Braak H., Bohl J. Close-meshed prevalence rates of different stages as a tool to uncover the rate of Alzheimer's disease-related neurofibrillary changes. Neuroscience 1995, 64:209-217.
123. Okamura N., Furumoto S., Fodero-Tavoletti M.T., Mulligan R.S., Harada R., Yates P., Pejoska S., Kudo Y., Masters C.L., Yanai K., Rowe C.C., Villemagne V.L. Non-invasive assessment of Alzheimer's disease neurofibrillary pathology using F-18-THK5105 PET. Brain 2014, 137:1762-1771.
124. Okuda M., Hijikuro I., Fujita Y., Wu X., Nakayama S., Sakata Y., Noguchi Y., Ogo M., Akasofu S., Ito Y., Soeda Y., Tsuchiya N., Tanaka N., Takahashi T., Sugimoto H. PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo. PLoS One 2015, 10:e0117511.
125. O'Leary J., Li Q., Marinec P., Blair L., Congdon E., Johnson A., Jinwal U., Koren J., Jones J., Kraft C., Peters M., Abisambra J., Duff K., Weeber E., Gestwicki J., Dickey C. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 2010, 5:45.
126. Onishi T., Matsumoto Y., Hattori M., Obayashi Y., Nakamura K., Yano T., Horiguchi T., Iwashita H. Early-onset cognitive deficits and axonal transport dysfunction in P301S mutant tau transgenic mice. Neurosci Res 2014, 80:76-85.
127. Ossenkoppele R., Schonhaut D.R., Baker S.L., O'Neil J.P., Janabi M., Ghosh P.M., Santos M., Miller Z.A., Bettcher B.M., Gorno-Tempini M.L., Miller B.L., Jagust W.J., Rabinovici G.D. Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy. Ann Neurol 2015, 77:338-342.
128. Paranjape S.R., Chiang Y.-M., Sanchez J.F., Entwistle R., Wang C.C.C., Oakley B.R., Gamblin T.C. Inhibition of tau aggregation by three Aspergillus nidulans secondary metabolites: 2, β-dihydroxyemodin, asperthecin, and asperbenzaldehyde. Planta Medica 2014, 80:77-85.
129. Pérez M., Hernández F., Gómez-Ramos A., Smith M., Perry G., Avila J. Formation of aberrant phosphotau fibrillar polymers in neural cultured cells. Eur J Biochem 2002, 269:1484-1489.
130. Pérez M., Valpuesta J.M., Medina M., Montejo De Garcini E., Avila J. Polymerization of τ into filaments in the presence of heparin: the minimal sequence required for τ-τ interaction. J Neurochem 1996, 67:1183-1190.
131. Perreault S., Bousquet O., Lauzon M., Paiement J., Leclerc N. Increased association between rough endoplasmic reticulum membranes and mitochondria in transgenic mice that express P301L tau. J Neuropathol Exptl Neurol 2009, 68:503-514.
132. 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 1987, 84:3033-3036.
133. Pfaffendorf M., Bruning T.A., Batink H.D., van Zwieten P.A. The interaction between methylene blue and the cholinergic system. Br J Pharmacol 1997, 122:95-98.
134. Phinney A.L., Horne P., Yang J., Janus C., Bergeron C., Westaway D. Mouse models of Alzheimer's disease: the long and filamentous road. Neurol Res 2003, 25:590-600.
135. Pickhardt M., Gazova Z., von Bergen M., Khlistunova I., Wang Y., Hascher A., Mandelkow E-M., Biernat J., Mandelkow E. Anthraquinones inhibit tau aggregation and dissolve Alzheimer paired helical filaments in vitro and in cells. J Biol Chem 2005, 280:3628-3635.
136. Pickhardt M., Larbig G., Khlistunova I., Coksezen A., Meyer B., Mandelkow E.M., Schmidt B., Mandelkow E. Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of τ aggregation and toxicity in vitro and in cells. Biochemistry 2007, 46:10016-10023.
137. Radde R., Duma C., Goedert M., Jucker M. The value of incomplete mouse models of Alzheimer's disease. Eur J Nuc Med Mol Imaging 2008, 35:70-74.
138. Ramsay R.R., Dunford C., Gillman P.K. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol 2007, 152:946-951.
139. Ramsden M., Kotilinek L., Forster C., Paulson J., McGowan E., SantaCruz K., Guimaraes A., Yue M., Lewis J., Carlson G., Hutton M., Ashe K.H. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 2005, 25:10637-10647.
140. Rankin C.A., Gamblin T.C. Assessing the toxicity of tau aggregation. J Alzheimer's Dis 2008, 14:411-416.
141. Reed L.A., Wszolek Z.K., Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001, 22:89-107.
142. Resch J.F., Lehr G.S., Wischik C.M. Design and synthesis of a potential affinity/cleaving reagent for beta-pleated sheet protein structures. Bioorg Med Chem Lett 1991, 1:519-522.
143. Salloway S., Sperling R., Fox N.C., Blennow K., Klunk W., Raskind M., Sabbagh M., Honig L.S., Porsteinsson A.P., Ferris S., Reichert M., Ketter N., Nejadnik B., Guenzler V., Miloslavsky M., Wang D., Lu Y., Lull J., Tudor I.C., Liu E., Grundman M., Yuen E., Black R., Brashear H.R. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. New Eng J Med 2014, 370:322-333.
144. Schneider A., Biernat J., von Bergen M., Mandelkow E., Mandelkow E-M. Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 1999, 38:3549-3558.
145. Schultz M.L., Tecedor L., Chang M., Davidson B.L. Clarifying lysosomal storage diseases. Trends Neurosci 2011, 34:401-410.
146. Schweers O., Mandelkow E.-M., Biernat J., Mandelkow E. Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein τ controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci USA 1995, 92:8463-8467.
147. Spires-Jones T.L., Friedman T., Pitstick R., Polydoro M., Roe A., Carlson G.A., Hyman B.T. Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett 2014, 562:63-68.
148. Stack C., Jainuddin S., Elipenahli C., Gerges M., Starkova N., Starkov A.A., Jové M., Portero-Otin M., Launay N., Pujol A., Kaidery N.A., Thomas B., Tampellini D., Beal M.F., Dumont M. Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet 2014, 23:3716-3732.
149. Taniguchi S., Suzuki N., Masuda M., Hisanaga S., Iwatsubo T., Goedert M., Hasegawa M. Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 2005, 280:7614-7623.
150. Tanzi RE: "New clarity" against Alzheimer's, Harvard Gazette; 2015. http://news.harvard.edu/gazette/story/2015/2005/new-clarity-against-alzheimers/.
151. Thal D.R., Rub U., Orantes M., Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 2002, 58:1791-1800.
152. Villemagne V.L., Fodero-Tavoletti M.T., Masters C.L., Rowe C.C. Tau imaging: early progress and future directions. Lancet Neurol 2015, 14:114-124.
153. Visarius T.M., Stucki J.W., Lauterburg B.H. Stimulation of respiration by methylene blue in rat liver mitochondria. FEBS Lett 1997, 412:157-160.
154. Vutskits L., Briner A., Klauser P., Gascon E., Dayer A.G., Kiss J.Z., Muller D., Licker M.J., Morel D.R. Adverse effects of methylene blue on the central nervous system. Anesthesiology 2008, 108:684-692.
155. Wein A.J., Benson G.S., Raezer D.M., Mulholland S.G. Oral methylene blue and the dissolution of renal calculi. J Urol 1976, 116:140-141.
156. Wilcock G.K., Esiri M.M. Plaques, tangles and dementia: a quantitative study. J Neurol Sci 1982, 56:343-356.
157. Wischik C.M., Crowther R.A., Stewart M., Roth M. Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol 1985, 100:1905-1912.
158. Wischik C.M., Edwards P.C., Lai R.Y.K., Gertz H.-J., Xuereb J.H., Paykel E.S., Brayne C., Huppert F.A., Mukaetova-Ladinska E.B., Mena R., Roth M., Harrington C.R. Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer's disease. Neurobiol Aging 1995, 16:409-431.
159. Wischik C.M., Edwards P.C., Lai R.Y.K., Roth M., Harrington C.R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci USA 1996, 93:11213-11218.
160. Wischik CM, Horsley D, Rickard JE, Harrington CR: Materials and methods relating to protein aggregation in neurodegenerative disease. US Patent:7335505; 2008.
161. Wischik C.M., Harrington C.R., Storey J.M.D. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 2014, 88:529-539.
162. Wischik C.M., Lai R.Y.K., Harrington C.R. Modelling prion-like processing of tau protein in Alzheimer's disease for pharmaceutical development. Brain microtubule associated proteins: modifications in disease 1997, 185-241. Harwood Academic Publishers, Amsterdam. J. Avila, R. Brandt, K.S. Kosik (Eds.).
163. Wischik C.M., Novak M., Edwards P.C., Klug A., Tichelaar W., Crowther R.A. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988, 85:4884-4888.
164. Wischik C.M., Novak M., Thøgersen H.C., Edwards P.C., Runswick M.J., Jakes R., Walker J.E., Milstein C., Roth M., Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer's disease. Proc Natl Acad Sci USA 1988, 85:4506-4510.
165. Wischik C.M., Staff R.T., Wischik D.J., Bentham P., Murray A.D., Storey J.M.D., Kook K.A., Harrington C.R. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease. J Alzheimer's Dis 2015, 44:705-720.
166. Wischik C.M., Theuring F., Harrington C.R. The molecular basis of tau protein pathology in Alzheimer's disease and related neurodegenerative dementias. Neurobiology of Alzheimer's disease 2001, 103-206. Oxford University Press, Oxford. D. Dawbarn, S.J. Allen (Eds.).
167. Yamashita M., Nonaka T., Arai T., Kametani F., Buchman V.L., Ninkina N., Bachurin S.O., Akiyama H., Goedert M., Hasegawa M. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett 2009, 583:2419-2424.
168. Yen S-H., Dickson D.W., Butler M., Shelanski M.L. Alzheimer's neurofibrillary tangles contain unique epitopes in common with the heat-stable microtubule-associated proteins tau and MAP2. Am J Pathol 1987, 126:81-91.
169. Yen S-H., Gaskin F., Fu S.M. Neurofibrillary tangles in senile dementia of the Alzheimer type share an antigenic determinant with intermediate filaments of the vimentin class. Am J Pathol 1983, 113:373-381.
170. Yoshiyama Y., Higuchi M., Zhang B., Huang S-M., Iwata N., Saido T.C., Maeda J., Suhara T., Trojanowski J.Q., Lee V.M.Y. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53:337-351.
171. Zilka N., Filipcik P., Koson P., Fialova L., Skrabana R., Zilkova M., Rolkova G., Kontsekova E., Novak M. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 2006, 580:3582-3588.