Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

BioMed Research International

Volumn 2016, Issue , 2016, Pages

  Panza, Francesco ^a,b   Solfrizzi, Vincenzo ^a   Seripa, Davide ^b   Imbimbo, Bruno P ^c   Lozupone, Madia ^a   Santamato, Andrea ^d   Zecca, Chiara ^a   Barulli, Maria Rosaria ^a   Bellomo, Antonello ^a   Pilotto, Alberto ^e   Daniele, Antonio ^f   Greco, Antonio ^b   Logroscino, Giancarlo ^a  

^a UNIVERSITY OF BARI   (Italy)

^b CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

^c CHIESI FARMACEUTICI S P A   (Italy)

^d UNIVERSITY OF FOGGIA   (Italy)

^e Laboratorio di Genetica EO Galliera   (Italy)

^f CATHOLIC UNIVERSITY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

4 BENZYL 2 METHYL 1,2,4 THIAZOLIDINE 3,5 DIONE; ACI 35; ALZHEIMER DISEASE VACCINE; AMYLOID BETA PROTEIN; ANTIMITOTIC AGENT; BIOLOGICAL MARKER; BMS 241027; BMS 986168; DAVUNETIDE; EPOTHILONE D; IPN 007; KEYHOLE LIMPET HEMOCYANIN; LEUCOMETHYLTHIONINIUM; LEUCOMETHYLTHIONINIUM DERIVATIVE; METHYLENE BLUE; METHYLTHIONINIUM; METHYLTHIONINIUM DERIVATIVE; PACLITAXEL; PEPTIDE; PHENOTHIAZINE DERIVATIVE; PROTEIN INHIBITOR; RG 7345; RO 6926496; SALICYLIC ACID DERIVATIVE; SALSALATE; TAU PROTEIN; TAU PROTEIN AGGREGATION INHIBITOR; TIDEGLUSIB; TPI 287; TRX 0237; UNCLASSIFIED DRUG; NEUROPROTECTIVE AGENT;

ACETYLATION; ALZHEIMER DISEASE; BRAIN BLOOD FLOW; COGNITION; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EFFICACY; DRUG METABOLISM; DRUG SAFETY; DRUG TARGETING; FRONTAL VARIANT FRONTOTEMPORAL DEMENTIA; HUMAN; NONHUMAN; PATHOPHYSIOLOGY; PHARMACOKINETICS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN AGGREGATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANTAGONISTS AND INHIBITORS; BRAIN; DRUG EFFECTS; EVIDENCE BASED MEDICINE; METABOLISM; MOLECULARLY TARGETED THERAPY; PROCEDURES; TREATMENT OUTCOME;

ALZHEIMER DISEASE; BRAIN; EVIDENCE-BASED MEDICINE; HUMANS; METHYLENE BLUE; MOLECULAR TARGETED THERAPY; NEUROPROTECTIVE AGENTS; TAU PROTEINS; TREATMENT OUTCOME;

EID: 84982860160     PISSN: 23146133     EISSN: 23146141     Source Type: Journal    
DOI: 10.1155/2016/3245935     Document Type: Review

References (175)

1. Alzheimer's Association, "2015 Alzheimer's disease facts and figures, "Alzheimers&Dementia, vol. 11, no. 3, pp. 332-384, 2015.
2. L. S. Schneider, F. Mangialasche, N. Andreasen et al., "Clinical trials and late-stage drug development for Alzheimer's disease: An appraisal from 1984 to 2014, " Journal of InternalMedicine, vol. 275, no. 3, pp. 251-283, 2014.
3. V. Frisardi, V. Solfrizzi, B. P. Imbimbo et al., "Towards diseasemodifying treatment of Alzheimer's disease: drugs targeting-amyloid, " Current Alzheimer Research, vol. 7, no. 1, pp. 40-55, 2010.
4. F. Panza, V. Solfrizzi, B. P. Imbimbo, and G. Logroscino, "Amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease: The point of no return?" Expert Opinion on BiologicalTherapy, vol. 14, no. 10, pp. 1465-1476, 2014.
5. C. M. Wischik, C. R. Harrington, and J. M. D. Storey, "Tauaggregation inhibitor therapy for Alzheimer's disease, " Biochemical Pharmacology, vol. 88, no. 4, pp. 529-539, 2014.
6. F. Panza, V. Solfrizzi, B. P. Imbimbo, R. Tortelli, A. Santamato, and G. Logroscino, "Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: The way forward, " Expert Review of Clinical Immunology, vol. 10, no. 3, pp. 405-419, 2014.
7. F. Panza, V. Frisardi, V. Solfrizzi et al., "Immunotherapy for Alzheimer's disease: from anti-amyloid to tau-based immunization strategies, " Immunotherapy, vol. 4, no. 2, pp. 213-238, 2012.
8. A. Takashima, "Tau aggregation is a therapeutic target for Alzheimer's disease, " Current Alzheimer Research, vol. 7, no. 8, pp. 665-669, 2010.
9. L. Buée, T.,Bussière, V. Buée-Scherrer, A. Delacourte, and P. R. Hof, "Tau protein isoforms, phosphorylation and role in neurodegenerative disorders, " Brain Research Reviews, vol. 33, no. 1, pp. 95-130, 2000.
10. G. L. Lace, S. B. Wharton, and P. G. Ince, "Abriefhistory of : The evolving view of the microtubule-associated protein in neurodegenerative diseases, " Clinical Neuropathology, vol. 26, no. 2, pp. 43-58, 2007.
11. C. M. Wischik, M. Novak, H. C. Thogersen et al., "Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease, " Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 12, pp. 4506-4510, 1988.
12. K. Iqbal, F. Liu, C.-X. Gong, and I. Grundke-Iqbal, "Tau in Alzheimer disease and related tauopathies, " Current Alzheimer Research, vol. 7, no. 8, pp. 656-664, 2010.
13. C. Bancher, C. Brunner, H. Lassmann et al., "Accumulation of abnormally phosphorylated precedes the formation of neurofibrillary tangles in Alzheimer's disease, " Brain Research, vol. 477, no. 1-2, pp. 90-99, 1989.
14. H. Braak, D. R. Thal, E. Ghebremedhin, and K. Del Tredici, "Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years, " Journal of Neuropathology & Experimental Neurology, vol. 70, no. 11, pp. 960-969, 2011.
15. H. Braak and E. Braak, "Neuropathological stageing of Alzheimer-related changes, " Acta Neuropathologica, vol. 82, no. 4, pp. 239-259, 1991.
16. H. Braak and E. Braak, "Evolution of the neuropathology of Alzheimer's disease, " Acta Neurologica Scandinavica, Supplement, vol. 93, no. 165, pp. 3-12, 1996.
17. H. Braak and E. Braak, "Frequency of stages of Alzheimerrelated lesions in different age categories, " Neurobiology of Aging, vol. 18, no. 4, pp. 351-357, 1997.
18. E. B. Mukaetova-Ladinska, F. Garcia-Siera, J. Hurt et al., "Staging of cytoskeletal and-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease, " The American Journal of Pathology, vol. 157, no. 2, pp. 623-636, 2000.
19. F. Liu, K. Iqbal, I. Grundke-Iqbal, G. W. Hart, and C.-X. Gong, "O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease, " Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 29, pp. 10804-10809, 2004.
20. M. Goedert, M. G. Spillantini, N. J. Cairns, and R. A. Crowther, "Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms, " Neuron, vol. 8, no. 1, pp. 159-168, 1992.
21. M. Novak, J. Kabat, and C. M. Wischik, "Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament, " The EMBO Journal, vol. 12, no. 1, pp. 365-370, 1993.
22. A. L. Guillozet-Bongaarts, F. Garcia-Sierra, M. R. Reynolds et al., "Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease, " Neurobiology of Aging, vol. 26, no. 7, pp. 1015-1022, 2005.
23. S.-W. Min, S.-H. Cho, Y. Zhou et al., "Acetylation of tau inhibits its degradation and contributes to tauopathy, " Neuron, vol. 67, no. 6, pp. 953-966, 2010.
24. M. Kolarova, F. Garciá-Sierra, A. Bartos, J. Ricny, and D. Ripova, "Structure and pathology of tau protein in Alzheimer disease, " International Journal ofAlzheimer'sDisease, vol. 2012, Article ID 731526, 13 pages, 2012.
25. P. Flores-Rodríguez, M. A. Ontiveros-Torres, M. C. Cárdenas-Aguayo et al., "The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer's disease, " Frontiers in Neuroscience, vol. 9, article 33, 2015.
26. Q. Zhang, X. Zhang, and A. Sun, "Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models, " Acta Neuropathologica, vol. 117, no. 6, pp. 687-697, 2009.
27. M. Saito, G. Chakraborty, R.-F. Mao, S.-M. Paik, C. Vadasz, and M. Saito, "Tau phosphorylation and cleavage in ethanolinduced neurodegeneration in the developing mouse brain, " Neurochemical Research, vol. 35, no. 4, pp. 651-659, 2010.
28. T. J. Cohen, J. L. Guo, D. E. Hurtado et al., "The acetylation of tau inhibits its function and promotes pathological tau aggregation, " Nature Communications, vol. 2, no. 1, article 252, 2011.
29. A. L. Guillozet-Bongaarts, M. E. Cahill, V. L. Cryns, M. R. Reynolds, R. W. Berry, and L. I. Binder, "Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo, " Journal of Neurochemistry, vol. 97, no. 4, pp. 1005-1014, 2006.
30. T. T. Rohn, R. A. Rissman, M. C. Davis, Y. E. Kim, C. W. Cotman, and E. Head, "Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain, " Neurobiology of Disease, vol. 11, no. 2, pp. 341-354, 2002.
31. C. Stadelmann, T. L. Deckwerth, A. Srinivasan et al., "Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease: evidence for apoptotic cell death, "The American Journal of Pathology, vol. 155, no. 5, pp. 1459-1466, 1999.
32. N. Sahara, S. Maeda, M. Murayama et al., "Assembly of two distinct dimers and higher-order oligomers from full-length tau, " European Journal of Neuroscience, vol. 25, no. 10, pp. 3020-3029, 2007.
33. T. Kimura, T. Fukuda, N. Sahara et al., "Aggregationof detergentinsoluble tau is involved in neuronal loss but not in synaptic loss, "The Journal of Biological Chemistry, vol. 285, no. 49, pp. 38692-38699, 2010.
34. M. Arrasate, S. Mitra, E. S. Schweitzer, M. R. Segal, and S. Finkbeiner, "Inclusion body formation reduces levels ofmutant huntingtin and the risk of neuronal death, " Nature, vol. 431, no. 7010, pp. 805-810, 2004.
35. D. C. Rubinsztein, "The roles of intracellular protein-degradation pathways in neurodegeneration, " Nature, vol. 443, no. 7113, pp. 780-786, 2006.
36. J. F. Diáz-Villanueva, R. Diáz-Molina, and V. Garciá-González, "Protein folding and mechanisms of proteostasis, " International Journal of Molecular Sciences, vol. 16, no. 8, pp. 17193-17230, 2015.
37. S. M. Pritchard, P. J. Dolan, A. Vitkus, and G. V. W. Johnson, "The toxicity of tau in Alzheimer disease: Turnover, targets and potential therapeutics, " Journal of Cellular and Molecular Medicine, vol. 15, no. 8, pp. 1621-1635, 2011.
38. B. Frost, R. L. Jacks, and M. I. Diamond, "Propagation of tau misfolding from the outside to the inside of a cell, " The Journal of Biological Chemistry, vol. 284, no. 19, pp. 12845-12852, 2009.
39. F. Clavaguera, I. Lavenir, B. Falcon, S. Frank, M. Goedert, and M. Tolnay, "Prion-like templated misfolding in tauopathies, " Brain Pathology, vol. 23, no. 3, pp. 342-349, 2013.
40. F. Clavaguera, T. Bolmont, R. A. Crowther et al., "Transmission and spreading of tauopathy in transgenic mouse brain, " Nature Cell Biology, vol. 11, no. 7, pp. 909-913, 2009.
41. A. A. Asuni, A. Boutajangout, D. Quartermain, and E. M. Sigurdsson, "Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements, " The Journal of Neuroscience, vol. 27, no. 34, pp. 9115-9129, 2007.
42. E. Masliah, E. Rockenstein, A. Adame et al., "Effects of-synuclein immunization in a mouse model of Parkinson's disease, " Neuron, vol. 46, no. 6, pp. 857-868, 2005.
43. P. V. Arriagada, J. H. Growdon, E. T. Hedley-Whyte, and B. T. Hyman, "Neurofibrillary tangles but not senile plaques parallel duration and severity ofAlzheimer's disease, " Neurology, vol. 42, no. 3, part 1, pp. 631-639, 1992.
44. K. Iqbal, C.-X. Gong, and F. Liu, "Microtubule-associated protein tau as a therapeutic target in Alzheimer's disease, " Expert Opinion onTherapeutic Targets, vol. 18, no. 3, pp. 307-318, 2014.
45. J. T. Pedersen and E. M. Sigurdsson, "Tau immunotherapy for Alzheimer's disease, " Trends in Molecular Medicine, vol. 21, no. 6, pp. 394-402, 2015.
46. K. Anand and M. Sabbagh, "Early investigational drugs targeting tau protein for the treatment of Alzheimer's disease, " Expert Opinion on Investigational Drugs, vol. 24, no. 10, pp. 1355-1360, 2015.
47. S. Khatoon, I. Grundke-Iqbal, and K. Iqbal, "Brain levels of microtubule-associated protein are elevated in Alzheimer's disease: A radioimmuno-slot-blot assay for nanograms of the protein, " Journal of Neurochemistry, vol. 59, no. 2, pp. 750-753, 1992.
48. L. Martin, X. Latypova, C. M. Wilsonet al., "Tauproteinkinases: involvement in Alzheimer's disease, " Ageing Research Reviews, vol. 12, no. 1, pp. 289-309, 2013.
49. C.-X. Gong and K. Iqbal, "Hyperphosphorylation of microtubule-associated protein tau: A promising therapeutic target for Alzheimer disease, " CurrentMedicinal Chemistry, vol. 15, no. 23, pp. 2321-2328, 2008.
50. F. Plattner, M. Angelo, and K. P. Giese, "The roles of cyclindependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation, "The Journal of Biological Chemistry, vol. 281, no. 35, pp. 25457-25465, 2006.
51. Y. Wen, E. Planel, M. Herman et al., "Interplay between cyclindependent kinase 5 and glycogen synthase kinase 3 mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing, " Journal of Neuroscience, vol. 28, no. 10, pp. 2624-2632, 2008.
52. R. V. Bhat, S. L. Budd Haeberlein, and J. Avila, "Glycogen synthase kinase 3: A drug target for CNS therapies, " Journal of Neurochemistry, vol. 89, no. 6, pp. 1313-1317, 2004.
53. E. Tolosa, I. Litvan, G. U. Höglinger et al., "A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy, " Movement Disorders, vol. 29, no. 4, pp. 470-478, 2014.
54. T. Del Ser, K. C. Steinwachs, H. J. Gertz et al., "Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: A pilot study, " Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 205-215, 2013.
55. S. Lovestone, M. Boada, B. Dubois et al., "ARGO investigators. A phase II trial of tideglusib in Alzheimer's disease, " Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 75-88, 2015.
56. K. Iqbal, F. Liu, and C.-X. Gong, "Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles, " Biochemical Pharmacology, vol. 88, no. 4, pp. 631-639, 2014.
57. S. Kins, A. Crameri, D. R. H. Evans, B. A. Hemmings, R. M. Nitsch, and J. Götz, "Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice, " The Journal of Biological Chemistry, vol. 276, no. 41, pp. 38193-38200, 2001.
58. T. Arendt, M. Holzer, R. Fruth, M. K. Brückner, and U. Gärtner, "Paired helical filament-like phosphorylation of tau, deposition of /A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A, " Neuroscience, vol. 69, no. 3, pp. 691-698, 1995.
59. M. Voronkov, S. P. Braithwaite, and J. B. Stock, "Phosphoprotein phosphatase 2A: A novel druggable target forAlzheimer's disease, " Future Medicinal Chemistry, vol. 3, no. 7, pp. 821-833, 2011.
60. K. Iqbal, A. D. C. Alonso, E. El-Akkad et al., "Significance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion, " Journal of Molecular Neuroscience, vol. 19, no. 1-2, pp. 95-99, 2002.
61. M. Medina and J. Avila, "Further understanding of tau phosphorylation: implications for therapy, " Expert Review of Neurotherapeutics, vol. 15, no. 1, pp. 115-122, 2015.
62. D. Butler, J. Bendiske, M. L. Michaelis, D. A. Karanian, and B. A. Bahr, "Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers, " European Journal of Pharmacology, vol. 562, no. 1-2, pp. 20-27, 2007.
63. B. Zhang, J. Carroll, J. Q. Trojanowski et al., "The microtubulestabilizing 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, vol. 32, no. 11, pp. 3601-3611, 2012.
64. Cortice biosciences announces results from studies evaluating pipeline candidates TPI 287 andCRT 001 in preclinicalmodels of tauopathies and Alzheimer's disease, 2014, https://globenewswire. com/news-release/2014/11/12/682514/10107850/en/Cortice-Biosciences-Announces-Results-From-Studies-Evaluating-Pipeline-Candidates-TPI-287-and-CRT-001-in-Preclinical-Models-of-Tauopathies-and-Alzheimer-s-Disease. html.
65. University of California San Francisco, "A safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy study of TPI-287 in Alzheimer's disease, " in ClinicalTrials. gov, InternetNational Library ofMedicine, Bethesda, MD, USA, 2000, ClinicalTrials. gov Identifier: NCT01966666, https://www. clinicaltrials. gov/ct/show/NCT01966666.
66. University of California San Francisco, "Safety Study of TPI-287 to Treat CBS and PSP (TPI-287-4RT), " in ClinicalTrials. gov, Internet National Library ofMedicine (US), Bethesda, MD, USA, ClinicalTrials. gov Identifier: NCT02133846, 2000, https://www. clinicaltrials. gov/ct/show/NCT02133846.
67. K. R. Brunden, B. Zhang, J. Carroll et al., "Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy, " The Journal of Neuroscience, vol. 30, no. 41, pp. 13861-13866, 2010.
68. Bristol-Myers Squibb, Study to Evaluate the Safety, Tolerability and the Effect of BMS-241027 on Cerebrospinal Fluid Biomarkers in Subjects with Mild Alzheimer's Disease, ClinicalTrials. gov Identifier: NCT01492374, InternetNational Library ofMedicine, Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/ NCT01056965.
69. I. Vulih-Shultzman, A. Pinhasov, S. Mandel et al., "Activitydependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mousemodel, " Journal of Pharmacology and Experimental Therapeutics, vol. 323, no. 2, pp. 438-449, 2007.
70. Y. Matsuoka, Y. Jouroukhin, A. J. Gray et al., "A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease, " Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 1, pp. 146-153, 2008.
71. Y. Jouroukhin, R. Ostritsky, Y. Assaf, G. Pelled, E. Giladi, and I. Gozes, "NAP (davunetide) modifies disease progression in amouse model of severe neurodegeneration: Protection against impairments in axonal transport, " Neurobiology of Disease, vol. 56, pp. 79-94, 2013.
72. A. L. Boxer, A. E. Lang, M. Grossman et al., "Davunetide in patients with progressive supranuclear palsy: A randomised, double-blind, placebo-controlled phase 2/3 trial, " The Lancet Neurology, vol. 13, no. 7, pp. 676-685, 2014.
73. University of California. San Francisco, Davunetide (AL-108) in Predicted Tauopathies-Pilot Study, ClinicalTrials. gov Identifier: NCT01056965, ClinicalTrials. gov. InternetNational Library ofMedicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT01056965.
74. "Allon therapeutics. Study to evaluate safety, tolerability, and effect of AL208 on mild cognitive impairment following coronary artery bypass graft surgery, " in ClinicalTrials. gov, Internet National Library of Medicine, Bethesda, Md, USA, 2000, ClinicalTrials. gov Identifier: NCT00404014, https://clinicaltrials. gov/ ct/show/NCT00404014.
75. H. Rosenmann, N. Grigoriadis, D. Karussis et al., "Tauopathylike abnormalities and neurologic deficits in mice immunized with neuronal tau protein, " Archives of Neurology, vol. 63, no. 10, pp. 1459-1467, 2006.
76. A. Boutajangout, D. Quartermain, and E. M. Sigurdsson, "Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model, " The Journal of Neuroscience, vol. 30, no. 49, pp. 16559-16566, 2010.
77. A. Boutajangout and T. Wisniewski, "Tau-based therapeutic approaches for Alzheimer's disease-a mini-review, " Gerontology, vol. 60, no. 5, pp. 381-385, 2014.
78. E. Kontsekova, N. Zilka, B. Kovacech, P. Novak, and M. Novak, "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, " Alzheimer's Research and Therapy, vol. 6, no. 4, article 44, 2014.
79. AxonNeuroscience SE, Safety Study ofAADvac1, A Tau Peptide-KLH-Conjugate Active Vaccine to Treat Alzheimer's Disease, ClinicalTrials. gov Identifier: NCT01850238, Internet National Library ofMedicine, Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT01850238.
80. S. Taniguchi, N. Suzuki, M. Masuda et al., "Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins, "The Journal of Biological Chemistry, vol. 280, no. 9, pp. 7614-7623, 2005.
81. Axon Neuroscience SE, 18-Months Safety Follow-Up Study of AADvac1, an Active Tau Vaccine for Alzheimer's Disease (FUNDAMANT), ClinicalTrials. gov Identifier: NCT02031198, Internet National Library of Medicine, Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT02031198.
82. Axon Neuroscience SE, 24 Months Safety and Efficacy Study of AADvac1 in Patients with Mild Alzheimer's Disease (ADAMANT), ClinicalTrials. gov Identifier: NCT02579252, ClinicalTrials. gov. Internet National Library of Medicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/ NCT02579252.
83. C. Theunis, N. Crespo-Biel, V. Gafner et al., "Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy, " PLoS ONE, vol. 8, no. 8, Article ID e72301, 2013.
84. R. Kayed, "Anti-tau oligomers passive vaccination for the treatment of Alzheimer disease, " Human Vaccines, vol. 6, no. 11, pp. 931-935, 2010.
85. R. Kayed, E. Head, J. L. Thompson et al., "Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis, " Science, vol. 300, no. 5618, pp. 486-489, 2003.
86. A. Boutajangout, J. Ingadottir, P. Davies, and E. M. Sigurdsson, "Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain, " Journal of Neurochemistry, vol. 118, no. 4, pp. 658-667, 2011.
87. E. E. Congdon, J. Gu, H. B. R. Sait, and E. M. Sigurdsson, "Antibody uptake into neurons occurs primarily via clathrindependent Fc. receptor endocytosis and is a prerequisite for acute tau protein clearance, "TheJournal of Biological Chemistry, vol. 288, no. 49, pp. 35452-35465, 2013.
88. J. Gu, E. E. Congdon, and E. M. Sigurdsson, "Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology, " The Journal of Biological Chemistry, vol. 288, no. 46, pp. 33081-33095, 2013.
89. L. Buée, T. Bussière, V. Buée-Scherrer, A. Delacourte, and P. R. Hof, "Tau protein isoforms, phosphorylation and role in neurodegenerative disorders, " Brain Research Reviews, vol. 33, no. 1, pp. 95-130, 2000.
90. L. Collin, B. Bohrmann, U. Göpfert, K. Oroszlan-Szovik, L. Ozmen, and F. Grüninger, "Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease, " Brain, vol. 137, no. 10, pp. 2834-2846, 2014.
91. H.-L. Roche, "A study of RO6926496 in healthy volunteers, " in ClinicalTrials. gov, Internet National Library of Medicine, Bethesda, Md, USA, ClinicalTrials. gov Identifier: NCT02281786, 2000, https://clinicaltrials. gov/ct/show/NCT02281786.
92. B.-M. Squibb, "Multiple ascending dose study of intravenously administered BMS-986168 in patients with progressive supranuclear palsy (CN002-003), " in ClinicalTrials. gov, Internet National Library ofMedicine, Bethesda, Md, USA, ClinicalTrials. gov Identifier: NCT02460094, 2000, https://clinicaltrials. gov/ ct/show/NCT02460094.
93. J. Bright, S. Hussain, V. Dang et al., "Human secreted tau increases amyloid-beta production, " Neurobiology of Aging, vol. 36, no. 2, pp. 693-709, 2015.
94. Bristol-Myers Squibb, A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study of Intravenously Administered BMS-986168 inHealthy Subjects, ClinicalTrials. gov Identifier: NCT02294851, Internet National Library of Medicine, Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/ NCT02294851.
95. K. Cisek, G. L. Cooper, C. J. Huseby, and J. Kuret, "Structure andmechanismof action of tau aggregation inhibitors, " Current Alzheimer Research, vol. 11, no. 10, pp. 918-927, 2014.
96. H. Hampel, L. S. Schneider, E. Giacobini et al., "Advances in the therapy of Alzheimer's disease: Targeting amyloid beta and tau and perspectives for the future, " Expert Review of Neurotherapeutics, vol. 15, no. 1, pp. 83-105, 2015.
97. C. M. Wischik, P. C. Edwards, R. Y. K. Lai, M. Roth, and C. R. Harrington, "Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines, " Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 20, pp. 11213-11218, 1996.
98. M. Necula, C. N. Chirita, and J. Kuret, "Cyanine dye N744 inhibits tau fibrillization by blocking filament extension: implications for the treatment of tauopathic neurodegenerative diseases, " Biochemistry, vol. 44, no. 30, pp. 10227-10237, 2005.
99. E. Chang, E. E. Congdon, N. S. Honson, K. E. Duff, and J. Kuret, "Structure-activity relationship of cyanine tau aggregation inhibitors, " Journal of Medicinal Chemistry, vol. 52, no. 11, pp. 3539-3547, 2009.
100. M. Pickhardt, J. Biernat, I. Khlistunova et al., "N-phenylamine derivatives as aggregation inhibitors in cell models of tauopathy, " CurrentAlzheimer Research, vol. 4, no. 4, pp. 397-402, 2007.
101. B. Bulic, M. Pickhardt, I. Khlistunova et al., "Rhodaninebased tau aggregation inhibitors in cell models of tauopathy, " Angewandte Chemie-International Edition, vol. 46, no. 48, pp. 9215-9219, 2007.
102. M. Pickhardt, G. Larbig, I. Khlistunova et al., "Phenylthiazolylhydrazide and its derivatives are potent inhibitors of. aggregation and toxicity in vitro and in cells, " Biochemistry, vol. 46, no. 35, pp. 10016-10023, 2007.
103. M. Pickhardt, Z. Gazova, M. Von Bergen et al., "Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells, "The Journal of Biological Chemistry, vol. 280, no. 5, pp. 3628-3635, 2005.
104. A. Crowe, W. Huang, C. Ballatore et al., "Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening, " Biochemistry, vol. 48, no. 32, pp. 7732-7745, 2009.
105. W. Li, J. B. Sperry, A. Crowe, J. Q. Trojanowski, A. B. Smith III, and V. M.-Y. Lee, "Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau, " Journal of Neurochemistry, vol. 110, no. 4, pp. 1339-1351, 2009.
106. M. C. Monti, L. Margarucci, R. Riccio, and A. Casapullo, "Modulation of tau protein fibrillization by oleocanthal, " Journal of Natural Products, vol. 75, no. 9, pp. 1584-1588, 2012.
107. F. Casamenti, C. Grossi, S. Rigacci, D. Pantano, I. Luccarini, and M. Stefani, "Oleuropein aglycone: A possible drug against degenerative conditions. In vivo evidence of its effectiveness against Alzheimer's disease, " Journal of Alzheimer's Disease, vol. 45, no. 3, pp. 679-688, 2015.
108. H. J. Wobst, A. Sharma, M. I. Diamond, E. E. Wanker, and J. Bieschke, "The green tea polyphenol-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios, " FEBS Letters, vol. 589, no. 1, pp. 77-83, 2015.
109. A. Crowe, M. J. James, Virginia M.-Y. Lee et al., "Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation, "The Journal of Biological Chemistry, vol. 288, no. 16, pp. 11024-11037, 2013.
110. G. Morris, G. Anderson, O. Deanet al., "Theglutathione system: A new drug target in neuroimmune disorders, " Molecular Neurobiology, vol. 50, no. 3, pp. 1059-1084, 2014.
111. K. N. Schafer, K. Cisek, C. J. Huseby, E. Chang, and J. Kuret, "Structural determinants of tau aggregation inhibitor potency, " The Journal of Biological Chemistry, vol. 288, no. 45, pp. 32599-32611, 2013.
112. F. Kees, "Dimethyl fumarate: A janus-faced substance" Expert Opinion on Pharmacotherapy, vol. 14, no. 11, pp. 1559-1567, 2013.
113. B. Bulic, M. Pickhardt, and E. Mandelkow, "Progress and developments in tau aggregation inhibitors for Alzheimer disease, " Journal of Medicinal Chemistry, vol. 56, no. 11, pp. 4135-4155, 2013.
114. B. Ahmad and L. J. Lapidus, "Curcumin prevents aggregation in.-synuclein by increasing reconfiguration rate, " The Journal of Biological Chemistry, vol. 287, no. 12, pp. 9193-9199, 2012.
115. S. Dolai, W. Shi, C. Corbo et al., "'Clicked' sugar-curcumin conjugate: modulator of amyloid-and tau peptide aggregation at ultralow concentrations, " American Chemical Society Chemical Neuroscience, vol. 2, no. 12, pp. 694-699, 2011.
116. M. Landau, M. R. Sawaya, K. F. Faull et al., "Towards a pharmacophore for amyloid, " PLoS Biology, vol. 9, no. 6, Article ID e1001080, 2011.
117. E. Akoury, M. Gajda, M. Pickhardt et al., "Inhibition of tau filament formation by conformational modulation, " Journal of the American Chemical Society, vol. 135, no. 7, pp. 2853-2862, 2013.
118. M. Masuda, N. Suzuki, S. Taniguchi et al., "Small molecule inhibitors of-synuclein filament assembly, " Biochemistry, vol. 45, no. 19, pp. 6085-6094, 2006.
119. U. Sengupta, M. J. Guerrero-Muñoz, D. L. Castillo-Carranza et al., "Pathological Interface between oligomeric alpha-synuclein and tau in synucleinopathies, " Biological Psychiatry, vol. 78, no. 10, pp. 672-683, 2015.
120. A. Crowe, C. Ballatore, E. Hyde, J. Q. Trojanowski, and V. M.-Y. Lee, "High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation, " Biochemical and Biophysical Research Communications, vol. 358, no. 1, pp. 1-6, 2007.
121. B. Bulic, M. Pickhardt, E.-M. Mandelkow, and E. Mandelkow, "Tau protein and tau aggregation inhibitors, " Neuropharmacology, vol. 59, no. 4-5, pp. 276-289, 2010.
122. S. Dähne, "Color and constitution: one hundred years of research, " Science, vol. 199, no. 4334, pp. 1163-1167, 1978.
123. R. H. Schirmer, H. Adler, M. Pickhardt, and E. Mandelkow, "'Lest we forget you-methylene blue. ', " Neurobiology of Aging, vol. 32, no. 12, pp. 2325. e7-2325. e16, 2011.
124. M. Wainwright and L. Amaral, "The phenothiazinium chromophore and the evolution of antimalarial drugs, " Tropical Medicine and International Health, vol. 10, no. 6, pp. 501-511, 2005.
125. N. F. Gaudette and J. W. Lodge, "Determination of methylene blue and leucomethylene blue in male and female Fischer 344 rat urine and B6C3F1 mouse urine, " Journal of Analytical Toxicology, vol. 29, no. 1, pp. 28-33, 2005.
126. B. Coulibaly, A. Zoungrana, F. P. Mockenhaupt et al., "Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: A randomised controlled trial, " PLoS ONE, vol. 4, no. 5, article e5318, 2009.
127. B. H. Harvey, I. Duvenhage, F. Viljoen et al., "Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues, " Biochemical Pharmacology, vol. 80, no. 10, pp. 1580-1591, 2010.
128. C. Peter, D. Hongwan, A. Küpfer, and B. H. Lauterburg, "Pharmacokinetics and organ distribution of intravenous and oral methylene blue, " European Journal of Clinical Pharmacology, vol. 56, no. 3, pp. 247-250, 2000.
129. T. Müller, "Methylene blue supravital staining: An evaluation of its applicability to the mammalian brain and pineal gland, " Histology and Histopathology, vol. 13, no. 4, pp. 1019-1026, 1998.
130. T. C. Baddeley, J. McCaffrey, J. M. D. Storey et al., "Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease, " Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 1, pp. 110-118, 2015.
131. C. R. Harrington, J. M. D. Storey, S. Clunas et al., "Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer disease, "The Journal of Biological Chemistry, vol. 290, no. 17, pp. 10862-10875, 2015.
132. V. Melis, M. Magbagbeolu, J. E. Rickard et al., "Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models, " Behavioural Pharmacology, vol. 26, no. 4, pp. 353-368, 2015.
133. C. A. Dickey, P. Ash, N. Klosaket al., "Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression, " Molecular Neurodegeneration, vol. 1, article 6, 2006.
134. U. K. Jinwal, Y. Miyata, J. Koren III et al., "Chemical manipulation of Hsp70 ATPase activity regulates tau stability, " The Journal of Neuroscience, vol. 29, no. 39, pp. 12079-12088, 2009.
135. J. C. O'Leary, Q. Li, P. Marinec et al., "Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden, "MolecularNeurodegeneration, vol. 5, no. 1, article 45, 2010.
136. E. E. Congdon, J. W. Wu, N. Myeku et al., "Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo, " Autophagy, vol. 8, no. 4, pp. 609-622, 2012.
137. L. Xie, W. Li, A. Winters, F. Yuan, K. Jin, and S.-H. Yang, "Methylene blue induces macroautophagy through 5' adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation, " Frontiers in Cellular Neuroscience, vol. 7, p. 56, 2013.
138. E. Akoury, M. Pickhardt, M. Gajda, J. Biernat, E. Mandelkow, and M. Zweckstetter, "Mechanistic basis of phenothiazinedriven inhibition of Tau aggregation, " Angewandte Chemie-International Edition, vol. 52, no. 12, pp. 3511-3515, 2013.
139. M. Pfaffendorf, T. A. Bruning, H. D. Batink, and P. A. Van Zwieten, "The interaction between methylene blue and the cholinergic system, " British Journal of Pharmacology, vol. 122, no. 1, pp. 95-98, 1997.
140. B. Mayer, F. Brunner, and K. Schmidt, "Inhibition of nitric oxide synthesis by methylene blue, " Biochemical Pharmacology, vol. 45, no. 2, pp. 367-374, 1993.
141. A. B. Chies, R. C. Custódio, G. de Souza, F. M. A. Corrêa, andO. C. M. Pereira, "Pharmacological evidence that methylene blue inhibits noradrenaline neuronal uptake in the rat vas deferens, " Polish Journal of Pharmacology, vol. 55, no. 4, pp. 573-579, 2003.
142. L. Vutskits, A. Briner, P. Klauser et al., "Adverse effects of methylene blue on the central nervous system, " Anesthesiology, vol. 108, no. 4, pp. 684-692, 2008.
143. R. R. Ramsay, C. Dunford, and P. K. Gillman, "Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction, " British Journal of Pharmacology, vol. 152, no. 6, pp. 946-951, 2007.
144. M. Necula, L. Breydo, S. Milton et al., "Methylene blue inhibits amyloid A oligomerization by promoting fibrillization, " Biochemistry, vol. 46, no. 30, pp. 8850-8860, 2007.
145. D. X. Medina, A. Caccamo, and S. Oddo, "Methylene blue reduces A levels and rescues early cognitive deficit by increasing proteasome activity, " Brain Pathology, vol. 21, no. 2, pp. 140-149, 2011.
146. S. Deiana, C. R. Harrington, C. M. Wischik, and G. Riedel, "Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine, " Psychopharmacology, vol. 202, no. 1-3, pp. 53-65, 2009.
147. P. D. Riha, J. C. Rojas, and F. Gonzalez-Lima, "Beneficial network effects of methylene blue in an amnestic model, " NeuroImage, vol. 54, no. 4, pp. 2623-2634, 2011.
148. V. Paban, C. Manrique, M. Filali, S. Maunoir-Regimbal, F. Fauvelle, and B. Alescio-Lautier, "Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model, " Neuropharmacology, vol. 76, pp. 68-79, 2014.
149. T. Mori, N. Koyama, T. Segawa et al., "Methylenebluemodulates-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice, "The Journal of Biological Chemistry, vol. 289, no. 44, pp. 30303-30317, 2014.
150. A. Zakaria, N. Hamdi, and R. M. Abdel-Kader, "Methylene blue improves brain mitochondrial ABAD functions and decreases A in a neuroinflammatory Alzheimer's disease mouse model, " Molecular Neurobiology, vol. 53, no. 2, pp. 1220-1228, 2016.
151. G. Roy Choudhury, A. Winters, R. M. Rich et al., "Methylene blue protects astrocytes against glucose oxygen deprivation by improving cellular respiration, " PLoS ONE, vol. 10, no. 4, Article ID e0123096, 2015.
152. Y. Wen, W. Li, E. C. Poteet et al., "Alternative mitochondrial electron transfer as a novel strategy for neuroprotection, " The Journal of Biological Chemistry, vol. 286, no. 18, pp. 16504-16515, 2011.
153. E. Poteet, A. Winters, L.-J. Yan et al., "Neuroprotective actions of methylene blue and its derivatives, " PLoS ONE, vol. 7, no. 10, article e48279, 2012.
154. C. Stack, S. Jainuddin, C. Elipenahli et al., "Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity, " Human Molecular Genetics, vol. 23, no. 14, Article ID ddu080, pp. 3716-3732, 2014.
155. K. Hochgräfe, A. Sydow, D. Matenia et al., "Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau, " Acta Neuropathologica Communications, vol. 3, article 25, 2015.
156. S. S. Mohideen, Y. Yamasaki, Y. Omata, L. Tsuda, and Y. Yoshiike, "Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies, " Scientific Reports, vol. 5, Article ID 10821, 2015.
157. A. S. AlMansouri, D. E. Lorke, S. M. Nurulain et al., "Methylene blue inhibits the function of 7-nicotinic acetylcholine receptors, " Central Nervous System & Neurological Disorders Drug Targets, vol. 11, no. 6, pp. 791-800, 2012.
158. T. M. Visarius, J. W. Stucki, and B. H. Lauterburg, "Stimulation of respiration by methylene blue in rat liver mitochondria, " FEBS Letters, vol. 412, no. 1, pp. 157-160, 1997.
159. F. van Bebber, D. Paquet, A. Hruscha, B. Schmid, and C. Haass, "Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish, " Neurobiology ofDisease, vol. 39, no. 3, pp. 265-271, 2010.
160. M. Hosokawa, T. Arai, M. Masuda-Suzukake et al., "Methylene Blue reduced abnormal tau accumulation in P301L tau transgenic mice, " PLoS ONE, vol. 7, no. 12, Article IDe52389, 2012.
161. T. L. Spires-Jones, T. Friedman, R. Pitstick et al., "Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510mousemodel of tauopathy, "Neuroscience Letters, vol. 562, pp. 63-68, 2014.
162. P. Cavaliere, J. Torrent, S. Prigent et al., "Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein, " Biochimica et Biophysica Acta, vol. 1832, no. 1, pp. 20-28, 2013.
163. M. Yamashita, T. Nonaka, T. Arai et al., "Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models, " FEBS Letters, vol. 583, no. 14, pp. 2419-2424, 2009.
164. T. Arai, M. Hasegawa, T. Nonoka et al., "Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy, " Neuropathology, vol. 30, no. 2, pp. 170-181, 2010.
165. I. R. A. MacKenzie, M. Neumann, N. J. Cairns, D. G. Munoz, and A. M. Isaacs, "Novel types of frontotemporal lobar degeneration: beyond Tau and TDP-43, " Journal of Molecular Neuroscience, vol. 45, no. 3, pp. 402-408, 2011.
166. C. M. Wischik, R. T. Staff, D. J. Wischik et al., "Tau aggregation inhibitor therapy: An exploratory phase 2 study in mild or moderate Alzheimer's disease, " Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 705-720, 2015.
167. TauRx Therapeutics Ltd, "Open label study of TRx0014 in Alzheimer's disease, " in ClinicalTrials. gov, Internet National Library of Medicine, Bethesda, Md, USA, ClinicalTrials. gov Identifier: NCT00684944, 2000, https://clinicaltrials. gov/ct/ show/NCT00684944.
168. T. Rager, A. Geoffroy, R. Hilfiker, and J. M. D. Storey, "The crystalline state of methylene blue: A zoo of hydrates, " Physical Chemistry Chemical Physics, vol. 14, no. 22, pp. 8074-8082, 2012.
169. V. Melis, C. Zabke, K. Stamer et al., "Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration, " Cellular and Molecular Life Sciences, vol. 72, no. 11, pp. 2199-2222, 2015.
170. TauRx Therapeutics, Safety Study of TRx0237 in PatientsAlready Taking Medications for Mild and Moderate Alzheimer's Disease, ClinicalTrials. gov Identifier: NCT01626391, ClinicalTrials. gov. Internet National Library of Medicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT01626391.
171. TauRx Therapeutics Ltd, Safety and Efficacy Study Evaluating TRx0237 in Subjects with Mild Alzheimer's Disease, ClinicalTrials. gov Identifier: NCT01689233, Internet National Library of Medicine, Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ ct/show/NCT01689233.
172. TauRx Therapeutics, Safety and Efficacy Study Evaluating TRx0237 in Subjects with Mild to Moderate Alzheimer's Disease, ClinicalTrials. gov Identifier: NCT01689246, ClinicalTrials. gov. Internet National Library of Medicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT01689246.
173. TauRx Therapeutics, Safety and Efficacy Study Evaluating TRx0237 in Subjects with Behavioral Variant Frontotemporal Dementia (bvFTD), ClinicalTrials. gov Identifier: NCT01626378, ClinicalTrials. gov. Internet National Library of Medicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/ show/NCT01626378.
174. TauRx Therapeutics, Open-Label Study of TRx0237 in Subjects With Alzheimer's Disease or Behavioral Variant Frontotemporal Dementia (bvFTD), ClinicalTrials. gov Identifier: NCT02245568, ClinicalTrials. gov. Internet National Library of Medicine (US), Bethesda, Md, USA, 2000, https://clinicaltrials. gov/ct/show/NCT02245568.
175. S.-W. Min, X. Chen, T. E. Tracy et al., "Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits, " Nature Medicine, vol. 21, no. 10, pp. 1154-1162, 2015.