686
Views
32
CrossRef citations to date
0
Altmetric
Reviews

Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium

, , , , , , , , & show all
Pages 259-277 | Received 06 Oct 2015, Accepted 06 Jan 2016, Published online: 26 Feb 2016

References

  • Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11(3):332–384.
  • Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275(3):251–283.
  • Frisardi V, Solfrizzi V, Imbimbo BP, et al. Towards disease-modifying treatment of Alzheimer’s disease: drugs targeting beta-amyloid. Curr Alzheimer Res. 2010;7(1):40–55.
  • Panza F, Solfrizzi V, Imbimbo BP, et al. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return? Expert Opin Biol Ther. 2014;14(10):1465–1476.
  • Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer’s disease. Biochem Pharmacol. 2014;88(4):529–539.
  • Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18(4):351–357.
  • Panza F, Frisardi V, Solfrizzi V, et al. Immunotherapy for Alzheimer’s disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy. 2012;4:213–238.
  • Lace GL, Wharton SB, Ince PG. A brief history of tau: the evolving view of the microtubule-associated protein tau in neurodegenerative diseases. Clin Neuropathol. 2007;26(2):43–58.
  • Wischik CM, Novak M, Thøgersen HC, et al. 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(12):4506–4510.
  • Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259.
  • Braak H, Braak E. Evolution of the neuropathology of Alzheimer’s disease. Acta Neurol Scand. 1996;94(S165):3–12.
  • Braak H, Thal DR, Ghebremedhin E, et al. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960–969.
  • Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, et al. 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(2):623–636.
  • Duyckaerts C. Tau pathology in children and young adults: can you still be unconditionally baptist? Acta Neuropathol. 2011;121(2):145–147.
  • Grober E, Dickson D, Sliwinski MJ, et al. Memory and mental status correlates of modified Braak staging. Neurobiol Aging. 1999;20(6):573–579.
  • Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362–381.
  • Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003;60(12):1696–1702.
  • Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207–216.
  • Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804.
  • Young AL, Oxtoby NP, Daga P, et al. A data-driven model of biomarker changes in sporadic Alzheimer’s disease. Brain. 2014;137(Pt 9):2564–2577.
  • Jack CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119–128.
  • Aisen PS, Petersen RC, Donohue MC, et al. Clinical core of the Alzheimer’s disease neuroimaging initiative: progress and plans. Alzheimers Dement. 2010;6(3):239–246.
  • Grundke-Iqbal I, Iqbal K, Tung YC, et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986;83(13):4913–4917.
  • Goedert M, Spillantini MG, Cairns NJ, et al. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8(1):159–168.
  • Wischik CM, Novak M, Edwards PC, et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4884–4888.
  • Novak M, Kabat J, Wischik CM. Molecular characterization of the minimal protease resistant tau unit of the Alzheimer’s disease paired helical filament. EMBO J. 1993;12(1):365–370.
  • Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, et al. Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging. 2005;26(7):1015–1022.
  • Yan SD, Chen X, Schmidt AM, et al. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci U S A. 1994;91(16):7787–7791.
  • Ledesma MD, Bonay P, Avila J. Tau protein from Alzheimer’s disease patients is glycated at its tubulin-binding domain. J Neurochem. 1995;65(4):1658–1664.
  • Reynolds MR, Berry RW, Binder LI. Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer’s disease. Biochemistry. 2005;44(5):1690–1700.
  • Reynolds MR, Reyes JF, Fu Y, et al. Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer’s disease and other tauopathies. J Neurosci. 2006;26(42):10636–10645.
  • Choudhary C, Kumar C, Gnad F, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–840.
  • Min S-W, Cho S-H, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010;67(6):953–966.
  • Arnold CS, Johnson GV, Cole RN, et al. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem. 1996;271(46):28741–28744.
  • Liu F, Iqbal K, Grundke-Iqbal I, et al. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA. 2004;101(29):10804–10809.
  • Perry G, Mulvihill P, Fried VA, et al. Immunochemical properties of ubiquitin conjugates in the paired helical filaments of Alzheimer disease. J Neurochem. 1989;52(5):1523–1528.
  • Iqbal K, Grundke-Iqbal I. Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer’s disease. Mol Neurobiol. 1991;5(2–4):399–410.
  • Kolarova M, García-Sierra F, Bartos A, et al. Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis. 2012;2012:731526.
  • Zhang Q, Zhang X, Sun A. Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models. Acta Neuropathol. 2009;117(6):687–697.
  • Saito M, Chakraborty G, Mao R-F, et al. Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. Neurochem Res. 2010;35(4):651–659.
  • Cohen TJ, Guo JL, Hurtado DE, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:252.
  • Stadelmann C, Deckwerth TL, Srinivasan A, et al. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am J Pathol. 1999;155(2):1459–1466.
  • Rohn TT, Rissman RA, Davis MC, et al. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis. 2002;11(2):341–354.
  • Kimura T, Fukuda T, Sahara N, et al. Aggregation of detergent-insoluble tau is involved in neuronal loss but not in synaptic loss. J Biol Chem. 2010;285(49):38692–38699.
  • Pritchard SM, Dolan PJ, Vitkus A, et al. The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics. J Cell Mol Med. 2011;15(8):1621–1635.
  • Arrasate M, Mitra S, Schweitzer ES, et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004;431(7010):805–810.
  • Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443(7113):780–786.
  • Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284(19):12845–12852.
  • Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11(7):909–913.
  • de Calignon A, Polydoro M, Suárez-Calvet M, et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron. 2012;73(4):685–697.
  • Asuni AA, Boutajangout A, Quartermain D, et al. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007;27(34):9115–9129.
  • Masliah E, Rockenstein E, Adame A, et al. Effects of α-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46(6):857–868.
  • Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007;8(2):101–112.
  • Iqbal K, Liu F, Gong C-X, et al. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol. 2009;118(1):53–69.
  • Brunden KR, Trojanowski JQ, Lee VM. Advances in tau-focused drug discovery for Alzheimer’s disease and related tauopathies. Nat Rev Drug Discov. 2009;8(10):783–793.
  • Andorfer C, Acker CM, Kress Y, et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005;25(22):5446–5454.
  • de Calignon A, Spires-Jones TL, Pitstick R, et al. Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy. J Neuropathol Exp Neurol. 2009;68(7):757–761.
  • Roberson ED, Scearce-Levie K, Palop JJ, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science. 2007;316(5825):750–754.
  • Vossel KA, Zhang K, Brodbeck J, et al. Tau reduction prevents A{beta}-induced defects in axonal transport. Science. 2010;330(6001):198.
  • Rhein V, Song X, Wiesner A, et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA. 2009;106(47):20057–20062.
  • Vershinin M, Carter BC, Razafsky DS, et al. Multiple-motor based transport and its regulation by tau. Proc Natl Acad Sci USA. 2007;104(1):87–92.
  • Morel M, Authelet M, Dedecker R, et al. Glycogen synthase kinase-3β and the p25 activator of cyclin dependent kinase 5 increase pausing of mitochondria in neurons. Neuroscience. 2010;167(4):1044–1056.
  • Ittner LM, Fath T, Ke YD, et al. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc Natl Acad Sci USA. 2008;105(41):15997–16002.
  • Ittner LM, Ke YD, Gotz J. Phosphorylated tau interacts with c-Jun N-terminal kinase interacting protein 1 (JIP1) in Alzheimer disease. J Biol Chem. 2009;284(31):20909–20916.
  • Eckert A, Schulz KL, Rhein V, et al. Convergence of amyloid-β and Tau pathologies on mitochondria in vivo. Mol Neurobiol. 2010;41(2–3):107–114.
  • Martin L, Latypova X, Wilson CM, et al. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev. 2013;12(1):289–309.
  • Iqbal K, Gong C-X, Liu F. Microtubule-associated protein tau as a therapeutic target in Alzheimer’s disease. Expert Opin Ther Targets. 2014;18(3):307–318.
  • Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med. 2015;21(6):394–402.
  • Anand K, Sabbagh M. Early investigational drugs targeting tau protein for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs. 2015;24(10):1355–1360.
  • Khatoon S, Grundke-Iqbal I, Iqbal K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer’s disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem. 1992;59(2):750–753.
  • Wen Y, Planel E, Herman M, et al. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3b mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci. 2008;28(10):2624–2632.
  • Tolosa E, Litvan I, Höglinger GU, et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord. 2014;29(4):470–478.
  • Del Ser T, Steinwachs KC, Gertz HJ, et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis. 2013;33(1):205–215.
  • Lovestone S, Boada M, Dubois B, et al. A phase II trial of tideglusib in Alzheimer’s disease. J Alzheimers Dis. 2015;45(1):75–88.
  • Kins S, Crameri A, Evans DR, et al. Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem. 2001;276(41):38193–38200.
  • Voronkov M, Braithwaite SP, Stock JB. Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease. Future Med Chem. 2011;3(7):821–833.
  • Medina M, Avila J. Further understanding of tau phosphorylation: implications for therapy. Expert Rev Neurother. 2015;15(1):115–122.
  • Wang X, Blanchard J, Kohlbrenner E, et al. The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J. 2010;24(11):4420–321.
  • Landrieu I, Smet-Nocca C, Amniai L, et al. Molecular implication of PP2A and Pin1 in the Alzheimer’s disease specific hyperphosphorylation of Tau. PLoS One. 2011;6(6):e21521.
  • Sontag J-M, Nunbhakdi-Craig V, Sontag E. Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells. J Biol Chem. 2013;288(38):27396–27405.
  • Butler D, Bendiske J, Michaelis M, et al. Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers. Eur J Pharmacol. 2007;562(1–2):20–27.
  • Zhang B, Carroll J, Trojanowski JQ, 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. J Neurosci. 2012;32(11):3601–3611.
  • Cortice biosciences announces results from studies evaluating pipeline candidates TPI 287 and CRT 001 in preclinical models of tauopathies and Alzheimer’s disease; 2014 [cited 2015 Sep 28]. Available from: http://globenewswire.com/newsrelease/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
  • Bassan M, Zamostiano R, et al. Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999;72(3):1283–1293.
  • Vulih-Shultzman I, Pinhasov A, Mandel S, et al. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther. 2007;323(2):438–449.
  • Gozes I, Giladi E, Pinhasov A, et al. Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a water maze. J Pharmacol Exp Ther. 2000;293(3):1091–1098.
  • Gozes I. NAP (davunetide) provides functional and structural neuroprotection. Curr Pharm Des. 2011;17(10):1040–1044.
  • Gozes I, Schirer Y, Idan-Feldman A, et al. NAP alpha-aminoisobutyric acid (IsoNAP). J Mol Neurosci. 2014;52(1):1–9.
  • Boxer AL, Lang AE, Grossman M, et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 2014;13:676–685.
  • Rosenmann H, Grigoriadis N, Karussis D, et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol. 2006;63(10):1459–1467.
  • Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci. 2010;30(49):16559–16566.
  • Kontsekova E, Zilka N, Kovacech B, et al. 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.
  • Theunis C, Crespo-Biel N, Gafner V, 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.
  • Boutajangout A, Ingadottir J, Davies P, et al. 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):658–667.
  • Congdon EE, Gu J, Sait HB, et al. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem. 2013;288(49):35452–35465.
  • Gu J, Congdon EE, Sigurdsson EM. Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology. J Biol Chem. 2013;288(46):33081–33095.
  • Kontsekova E, Ivanovova N, Handzusova M, et al. Chaperone-like antibodies in neurodegenerative tauopathies: implication for immunotherapy. Cell Mol Neurobiol. 2009;29(6–7):793–798.
  • Taniguchi T, Sumida M, Hiraoka S, et al. Effects of different anti-tau antibodies on tau fibrillogenesis: RTA-1 and RTA-2 counteract tau aggregation. FEBS Lett. 2005;579(6):1399–1404.
  • Zilka N, Kontsekova E, Novak M. Chaperone-like antibodies targeting misfolded tau protein: new vistas in the immunotherapy of neurodegenerative foldopathies. J Alzheimers Dis. 2008;15:169–179.
  • Kontsekova E, Zilka N, Kovacech B, et al. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther. 2014;6(4):45.
  • Buée L, Bussière T, Buée-Scherrer V, et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33(1):95–130.
  • Collin L, Bohrmann B, Göpfert U, et al. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain. 2014;137(Pt 10):2834–2846.
  • Bright J, Hussain S, Dang V, et al. Human secreted tau increases amyloid-beta production. Neurobiol Aging. 2015;36(2):693–709.
  • Cisek K, Cooper GL, Huseby CJ, et al. Structure and mechanism of action of tau aggregation inhibitors. Curr Alzheimer Res. 2014;11(10):918–927.
  • Taniguchi S, Suzuki N, Masuda M, et al. Inhibition of heparin-induced Tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem. 2005;280(9):7614–7623.
  • Wobst HJ, Sharma A, Diamond MI, et al. The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett. 2015;589(1):77–83.
  • Crowe A, Ballatore C, Hyde E, et al. High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation. Biochem Biophys Res Commun. 2007;358(1):1–6.
  • Wischik CM, Edwards PC, Lai RY, et al. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A. 1996;93(20):11213–11218.
  • Chirita C, Necula M, Kuret J. Ligand-dependent inhibition and reversal of Tau filament formation. Biochemistry. 2004;43(10):2879–2887.
  • Necula M, Chirita CN, Kuret J. Cyanine dye N744 inhibits tau fibrillization by blocking filament extension: implications for the treatment of tauopathic neurodegenerative diseases. Biochemistry. 2005;44(30):10227–10237.
  • Chang E, Congdon EE, Honson NS, et al. Structure-activity relationship of cyanine tau aggregation inhibitors. J Med Chem. 2009;52(11):3539–3547.
  • Pickhardt M, Biernat J, Khlistunova I, et al. N-phenylamine derivatives as aggregation inhibitors in cell models of tauopathy. Curr Alzheimer Res. 2007;4(4):397–402.
  • Bulic B, Pickhardt M, Mandelkow E-M, et al. Tau protein and tau aggregation inhibitors. Neuropharmacology. 2010;59(4–5):276–289.
  • Bulic B, Pickhardt M, Khlistunova I, et al. Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem Int Ed Engl. 2007;46(48):9215–9219.
  • Schafer KN, Cisek K, Huseby CJ, et al. Structural determinants of Tau aggregation inhibitor potency. J Biol Chem. 2013;288(45):32599–32611.
  • Larbig G, Pickhardt M, Lloyd DG, et al. Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: a ligand based approach results in successful scaffold hopping. Curr Alzheimer Res. 2007;4(3):315–323.
  • Pickhardt M, Larbig G, Khlistunova I, et al. Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells. Biochemistry. 2007;46:10016–10023.
  • Pickhardt M, Gazova Z, von Bergen M, et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer’s paired helical filaments in vitro and in cells. J Biol Chem. 2005;280(5):3628–3635.
  • Crowe A, Huang W, Ballatore C, et al. Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry. 2009;48(32):7732–7745.
  • Ballatore C, Crowe A, Piscitelli F, et al. Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo properties. Bioorg Med Chem. 2012;20(14):4451–4461.
  • Li W, Sperry JB, Crowe A, et al. Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem. 2009;110(4):1339–1351.
  • Monti MC, Margarucci L, Riccio R, et al. Modulation of tau protein fibrillization by oleocanthal. J Nat Prod. 2012;75(9):1584–1588.
  • Casamenti F, Grossi C, Rigacci S, et al. Oleuropein aglycone: a possible drug against degenerative conditions. In vivo evidence of its effectiveness against Alzheimer’s disease. J Alzheimers Dis. 2015;45(3):679–688.
  • George RC, Lew J, Graves DJ. Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer’s disease pathogenesis. J Alzheimers Dis. 2013;36(1):21–40.
  • Peterson DW, George RC, Scaramozzino F, et al. Cinnamon extract inhibits tau aggregation associated with Alzheimer’s disease in vitro. J Alzheimers Dis. 2009;17(3):585–597.
  • Paranjape SR, Chiang Y-M, Sanchez JF, et al. Inhibition of Tau aggregation by three Aspergillus nidulans secondary metabolites: 2,ω-dihydroxyemodin, asperthecin, and asperbenzaldehyde. Planta Med. 2014;80(1):77–85.
  • Calcul L, Zhang B, Jinwal UK, et al. Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease. Future Med Chem. 2012;4(13):1751–1761.
  • Gao J-M, Yang S-X, Qin J-C. Azaphilones: chemistry and biology. Chem Rev. 2013;113(7):4755–4811.
  • Paranjape SR, Riley AP, Somoza AD, et al. Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. ACS Chem Neurosci. 2015;6(5):751–760.
  • Crowe A, James MJ, Lee VM, et al. Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. J Biol Chem. 2013;288(16):11024–11037.
  • Morris G, Anderson G, Dean O, et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol. 2014;50(3):1059–1084.
  • Chang E, Honson NS, Bandyopadhyay B, et al. Modulation and detection of tau aggregation with small-molecule ligands. Curr Alzheimer Res. 2009 Oct;6(5):409–414.
  • Bulic B, Pickhardt M, Mandelkow E. Progress and developments in tau aggregation inhibitors for Alzheimer disease. J Med Chem. 2013;56(11):4135–4155.
  • Ahmad B, Chen Y, Lapidus LJ. Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion. Proc Natl Acad Sci U S A. 2012;109(7):2336–2341.
  • Ahmad B, Lapidus LJ. Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J Biol Chem. 2012;287(12):9193–9199.
  • Dolai S, Shi W, Corbo C, et al. “Clicked” sugar-curcumin conjugate: modulator of amyloid-β and tau peptide aggregation at ultralow concentrations. ACS Chem Neurosci. 2011;2(12):694–699.
  • Sinha S, Lopes DH, Du Z, et al. Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins. J Am Chem Soc. 2011;133(42):16958–16969.
  • Attar A, Ripoli C, Riccardi E, et al. Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers. Brain. 2012;135(12):3735–3748.
  • Acharya S, Safaie BM, Wongkongkathep P, et al. Molecular basis for preventing α-synuclein aggregation by a molecular tweezer. J Biol Chem. 2014;289(15):10727–10737.
  • Landau M, Sawaya MR, Faull KF, et al. Towards a pharmacophore for amyloid. PLoS Biol. 2011;9(6):e1001080.
  • Akoury E, Gajda M, Pickhardt M, et al. Inhibition of tau filament formation by conformational modulation. J Am Chem Soc. 2013;135(7):2853–2862.
  • Masuda M, Suzuki N, Taniguchi S, et al. Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry. 2006;45(19):6085–6094.
  • Dähne S. Color and constitution: one hundred years of research. Science. 1978;199(4334):1163–1167.
  • Schirmer RH, Adler H, Pickhardt M, et al. Lest we forget you–methylene blue. Neurobiol Aging. 2011;32(12):2325.e7–2325.e16.
  • Wainwright M, Amaral L. The phenothiazinium chromophore and the evolution of antimalarial drugs. Trop Med Int Health. 2005;10(6):501–511.
  • Gaudette NF, Lodge JW. Determination of methylene blue and leucomethylene blue in male and female Fischer 344 rat urine and B6C3F1 mouse urine. J Anal Toxicol. 2005;29(1):28–33.
  • Coulibaly B, Zoungrana A, Mockenhaupt FP, et al. Strong gametocytocidal effect of methylene blue-based combination therapy against falciparum malaria: a randomised controlled trial. PLoS One. 2009;4(5):e5318.
  • Harvey BH, Duvenhage I, Viljoen F, 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. Biochem Pharmacol. 2010;80(10):1580–1591.
  • Peter C, Hongwan D, Küpfer A, et al. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000;56(3):247–250.
  • Müller T. Methylene blue supravital staining: an evaluation of its applicability to the mammalian brain and pineal gland. Histopathology. 1998;13(4):1019–1026.
  • Baddeley TC, McCaffrey J, Storey JM, et al. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J Pharmacol Exp Ther. 2015;352(1):110–118.
  • Harrington CR, Storey JM, Clunas S, et al. Cellular models of aggregation-dependent template-directed proteolysis to characterize Tau aggregation inhibitors for treatment of Alzheimer disease. J Biol Chem. 2015;290(17):10862–10875.
  • Melis V, Magbagbeolu M, Rickard JE, et al. Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol. 2015;26(4):353–368.
  • Dickey C, Ash P, Klosak N, et al. Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegeneration. 2006;1:6.
  • Jinwal UK, Miyata Y, Koren J 3rd, et al. Chemical manipulation of Hsp70 ATPase activity regulates tau stability. J Neurosci. 2009;29(39):12079–12088.
  • O’Leary J, Li Q, Marinec P, et al. Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener. 2010;5:45.
  • Congdon EE, Wu JW, Myeku N, et al. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012;8(4):609–622.
  • Xie L, Li W, Winters A, et al. Methylene blue induces macroautophagy through 5ʹ adenosine monophosphate-activated protein kinase pathway to protect neurons from serum deprivation. Front Cell Neurosci. 2013;7:56.
  • Akoury E, Pickhardt M, Gajda M, et al. Mechanistic basis of phenothiazine-driven inhibition of tau aggregation. Angewandte Chemie Int Ed. 2013;52(12):3511–3515.
  • Pfaffendorf M, Bruning TA, Batink HD, et al. The interaction between methylene blue and the cholinergic system. Br J Pharmacol. 1997;122(1):95–98.
  • Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol. 1993;45(2):367–374.
  • Chies AB, Custódio RC, de Souza GL, et al. Pharmacological evidence that methylene blue inhibits noradrenaline neuronal uptake in the rat vas deferens. Pol J Pharmacol. 2003;55(4):573–579.
  • Vutskits L, Briner A, Klauser P, et al. Adverse effects of methylene blue on the central nervous system. Anesthesiology. 2008;108(4):684–692.
  • Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007;152(6):946–951.
  • Necula M, Breydo L, Milton S, et al. Methylene blue inhibits amyloid Abeta oligomerization by promoting fibrillization. Biochemistry. 2007;46(30):8850–8860.
  • Medina DX, Caccamo A, Oddo S. Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol. 2011;21(2):140–149.
  • Deiana S, Harrington CR, Wischik CM, et al. Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl). 2009;202(1–3):53–65.
  • Riha PD, Rojas JC, Gonzalez-Lima F. Beneficial network effects of methylene blue in an amnestic model. Neuroimage. 2011;54(4):2623–2634.
  • Paban V, Manrique C, Filali M, et al. Therapeutic and preventive effects of methylene blue on Alzheimer’s disease pathology in a transgenic mouse model. Neuropharmacology. 2014;76(Pt A):68–79.
  • Mori T, Koyama N, Segawa T, et al. Methylene blue modulates β-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice. J Biol Chem. 2014;289(44):30303–30317.
  • Zakaria A, Hamdi N, Abdel-Kader RM. Methylene blue improves brain mitochondrial ABAD functions and decreases Aβ in a neuroinflammatory Alzheimer’s disease mouse model. Mol Neurobiol. 2015 [Epub ahead of print]. doi:10.1007/s12035-014-9088-8.
  • Roy Choudhury G, Winters A, Rich RM, et al. Methylene blue protects astrocytes against glucose oxygen deprivation by improving cellular respiration. PLoS One. 2015;10(4):e0123096.
  • Wen Y, Li W, Poteet EC, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011;286(18):16504–16515.
  • Poteet E, Winters A, Yan LJ, et al. Neuroprotective actions of methylene blue and its derivatives. PLoS One. 2012;7(10):e48279.
  • Stack C, Jainuddin S, Elipenahli C, et al. Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet. 2014;23(14):3716–3732.
  • Hochgräfe K, Sydow A, Matenia D, et al. Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathol Commun. 2015;3:25.
  • Mohideen SS, Yamasaki Y, Omata Y, et al. Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies. Sci Rep. 2015;5:10821.
  • Al Mansouri AS, Lorke DE, Nurulain SM, et al. Methylene blue inhibits the function of α7-nicotinic acetylcholine receptors. CNS Neurol Disord Drug Targets. 2012;11(6):791–800.
  • Visarius TM, Stucki JW, Lauterburg BH. Stimulation of respiration by methylene blue in rat liver mitochondria. FEBS Lett. 1997;412(1):157–160.
  • van Bebber F, Paquet D, Hruscha A, et al. Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiol Dis. 2010 Sep;39(3):265–271.
  • Hosokawa M, Arai T, Masuda-Suzukake M, et al. Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. PLoS One. 2012;7(12):e52389.
  • Spires-Jones TL, Friedman T, Pitstick R, et al. Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett. 2014;562:63–68.
  • Cavaliere P, Torrent J, Prigent S, et al. Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein. Biochim Biophys Acta. 2013;1832(1):20–28.
  • Yamashita M, Nonaka T, Arai T, et al. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett. 2009;583(14):2419–2424.
  • Arai T, Hasegawa M, Nonoka T, et al. Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology. 2010;30(2):170–181.
  • Mackenzie IRA, Neumann M, Cairns NJ, et al. Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci. 2011;45(3):402–408.
  • Sontag EM, Lotz GP, Agrawal N, et al. Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models. J Neurosci. 2012;32(32):11109–11119.
  • Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis. 2015;44(2):705–720.
  • Rager T, Geoffroy A, Hilfiker R, et al. The crystalline state of methylene blue: a zoo of hydrates. Phys Chem Chem Phys. 2012;14(22):8074–8082.
  • Melis V, Zabke C, Stamer K, et al. 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(11):2199–2222.
  • Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurochem. 2007;25(1):59–68.
  • Medina M, Avila J. New insights into the role of glycogen synthase kinase-3 in Alzheimer’s disease. Expert Opin Ther Targets. 2014;18(1):69–77.
  • Min S-W, Chen X, Tracy TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21:1154–1162. doi:10.1038/nm.3951.
  • Sigurdsson EM. Tau immunotherapy and imaging. Neurodegener Dis. 2014;13(2–3):103–106.
  • Castillo-Carranza DL, Sengupta U, Guerrero-Muñoz MJ, et al. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014;34(12):4260–4272.
  • Sutphen CL, Jasielec MS, Shah AR, et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol. 2015;72(9):1029–1042.
  • Vos SJ, Xiong C, Visser PJ, et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 2013;12(10):957–965.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.