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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2015

Open Access 01-12-2015 | Research

Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau

Authors: Katja Hochgräfe, Astrid Sydow, Dorthe Matenia, Daniela Cadinu, Stefanie Könen, Olga Petrova, Marcus Pickhardt, Petra Goll, Fabio Morellini, Eckhard Mandelkow, Eva-Maria Mandelkow

Published in: Acta Neuropathologica Communications | Issue 1/2015

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Abstract

Introduction

Neurofibrillary tangles (NFT) composed of Tau are hallmarks of neurodegeneration in Alzheimer disease. Transgenic mice expressing full-length pro-aggregant human Tau (2N4R Tau-ΔK280, termed TauΔK) or its repeat domain (TauRD-ΔK280, TauRDΔK) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRDΔK assembles into NFT concomitant with neuronal death, TauΔK accumulates into Tau pretangles without overt neuronal loss. Both forms cause a comparable cognitive decline (with onset at 10mo and 12mo, respectively), which is rescued upon switch-off of transgene expression. Since methylene blue (MB) is able to inhibit Tau aggregation in vitro, we investigated whether MB can prevent or rescue Tau-induced cognitive impairments in our mouse models. Both types of mice received MB orally using different preventive and therapeutic treatment protocols, initiated either before or after disease onset. The cognitive status of the mice was assessed by behavior tasks (open field, Morris water maze) to determine the most successful conditions for therapeutic intervention.

Results

Preventive and therapeutic MB application failed to avert or recover learning and memory deficits of TauRDΔK mice. Similarly, therapeutic MB treatment initiated after onset of cognitive impairments was ineffective in TauΔK mice. In contrast, preventive MB application starting before onset of functional deficits preserved cognition of TauΔK mice. Beside improved learning and memory, MB-treated TauΔK mice showed a strong decrease of insoluble Tau, a reduction of conformationally changed (MC1) and phosphorylated Tau species (AT180, PHF1) as well as an upregulation of protein degradation systems (autophagy and proteasome). This argues for additional pleiotropic effects of MB beyond its properties as Tau aggregation inhibitor.

Conclusions

Our data support the use of Tau aggregation inhibitors as potential drugs for the treatment of AD and other tauopathies and highlights the need for preventive treatment before onset of cognitive impairments.
Appendix
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Literature
1.
2.
Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M (2013) A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer’s disease. J Alzheimer’s Dis 35:349–361, doi: 10.3233/JAD-122140
3.
Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712, doi: 10.1038/nrd3505CrossRefPubMed
4.
Wischik CM, Harrington CR, Storey JM (2014) Tau-aggregation inhibitor therapy for Alzheimer’s disease. Biochem Pharmacol 88:529–539, doi: 10.1016/j.bcp.2013.12.008CrossRefPubMed
5.
Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, Parisi JE, Hyman BT (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24, doi: 10.1002/ana.410410106CrossRefPubMed
6.
Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931CrossRefPubMed
7.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580, doi: 10.1002/ana.410300410CrossRefPubMed
8.
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351, doi:S0896-6273(07)00030-XCrossRefPubMed
9.
Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22:9340–9351, doi:22/21/9340PubMed
10.
Schindowski K, Bretteville A, Leroy K, Begard S, Brion JP, Hamdane M, Buee L (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599–616, doi:S0002-9440(10)62740-XCrossRefPubMedCentralPubMed
11.
Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405, doi: 10.1038/78078CrossRefPubMed
12.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481, doi:309/5733/476CrossRefPubMedCentralPubMed
13.
Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F (2005) Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2 N transgenic mice. J Biol Chem 280:3963–3973, doi: 10.1074/jbc.M409876200CrossRefPubMed
14.
Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D’Hooge R, Alzheimer C, Mandelkow EM (2011) Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 31:2511–2525, doi:31/7/2511CrossRefPubMed
15.
Van der Jeugd A, Hochgrafe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L, Balschun D, D’Hooge R, Mandelkow EM (2012) Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol 123:787–805, doi: 10.1007/s00401-012-0987-3CrossRefPubMed
16.
Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schonig K, Bujard H, Haemisch A, Mandelkow E, Zhou L, Rune G, Mandelkow EM (2007) The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282:31755–31765, doi:M705282200CrossRefPubMed
17.
Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O, Schonig K, Bujard H, Mandelkow E, Zhou L, Rune G, Mandelkow EM (2008) The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci 28:737–748, doi:28/3/737CrossRefPubMed
18.
Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 64:414–421, doi: 10.1086/302256CrossRefPubMedCentralPubMed
19.
Van Swieten JC, Bronner IF, Azmani A, Severijnen LA, Kamphorst W, Ravid R, Rizzu P, Willemsen R, Heutink P (2007) The DeltaK280 mutation in MAP tau favors exon 10 skipping in vivo. J Neuropathol Exp Neurol 66:17–25, doi:10.1097/nen.0b013e31802c39a400005072-200701000-00003CrossRefPubMed
20.
Momeni P, Pittman A, Lashley T, Vandrovcova J, Malzer E, Luk C, Hulette C, Lees A, Revesz T, Hardy J, de Silva R (2009) Clinical and pathological features of an Alzheimer’s disease patient with the MAPT Delta K280 mutation. Neurobiol Aging 30:388–393, doi: 10.1016/j.neurobiolaging.2007.07.013CrossRefPubMedCentralPubMed
21.
Bulic B, Pickhardt M, Mandelkow E (2013) Progress and developments in tau aggregation inhibitors for Alzheimer disease. J Med Chem 56:4135–4155, doi: 10.1021/jm3017317CrossRefPubMed
22.
Crowe A, Ballatore C, Hyde E, Trojanowski JQ, Lee VM (2007) High throughput screening for small molecule inhibitors of heparin-induced tau fibril formation. Biochem Biophys Res Commun 358:1–6, doi: 10.1016/j.bbrc.2007.03.056CrossRefPubMedCentralPubMed
23.
Pickhardt M, von Bergen M, Gazova Z, Hascher A, Biernat J, Mandelkow EM, Mandelkow E (2005) Screening for inhibitors of tau polymerization. Curr Alzheimer Res 2:219–226CrossRefPubMed
24.
Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M (2005) Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 280:7614–7623, doi:M408714200CrossRefPubMed
25.
Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR (1996) Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl Acad Sci U S A 93:11213–11218CrossRefPubMedCentralPubMed
26.
Sontag EM, Lotz GP, Agrawal N, Tran A, Aron R, Yang G, Necula M, Lau A, Finkbeiner S, Glabe C, Marsh JL, Muchowski PJ, Thompson LM (2012) Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models. J Neurosci 32:11109–11119, doi: 10.1523/JNEUROSCI.0895-12.2012CrossRefPubMedCentralPubMed
27.
Arai T, Hasegawa M, Nonoka T, Kametani F, Yamashita M, Hosokawa M, Niizato K, Tsuchiya K, Kobayashi Z, Ikeda K, Yoshida M, Onaya M, Fujishiro H, Akiyama H (2010) Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology 30:170–181, doi: 10.1111/j.1440-1789.2009.01089.xCrossRefPubMed
28.
Necula M, Breydo L, Milton S, Kayed R, van der Veer WE, Tone P, Glabe CG (2007) Methylene blue inhibits amyloid Abeta oligomerization by promoting fibrillization. Biochemistry 46:8850–8860, doi: 10.1021/bi700411kCrossRefPubMed
29.
Cavaliere P, Torrent J, Prigent S, Granata V, Pauwels K, Pastore A, Rezaei H, Zagari A (2013) Binding of methylene blue to a surface cleft inhibits the oligomerization and fibrillization of prion protein. Biochim Biophys Acta 1832:20–28, doi: 10.1016/j.bbadis.2012.09.005CrossRefPubMed
30.
Schirmer RH, Adler H, Pickhardt M, Mandelkow E (2011) “Lest we forget you--methylene blue…”. Neurobiol Aging 32:2325 e2327-2316. doi:10.1016/j.neurobiolaging.2010.12.012S0197-4580(10)00529-4
31.
Oz M, Lorke DE, Petroianu GA (2009) Methylene blue and Alzheimer’s disease. Biochem Pharmacol 78:927–932, doi:10.1016/j.bcp.2009.04.034S0006-2952(09)00335-9CrossRefPubMed
32.
Wischik CM, Bentham P, Wischik DJ, Seng KM (2008) O3-04-07: Tau aggregation inhibitor (TAI) therapy with rember™ arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks. Paper presented at the Alzheimer’s Association International Conference. Alzheimer’s Association International Conference, Chicago IL, United States
33.
Baddeley TC, McCaffrey J, MDS J, Cheung JK, Melis V, Horsley D, Harrington CR, Wischik CM (2015) Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer‘s disease. J Pharmacol Exp Ther 352:110–118, doi:10.1124/jpet.114.219352CrossRefPubMed
34.
Wischik C, Siew Choon T, Say Way S, Logan S (2014) TauRx.com About LMTX™ for Alzheimer’s. TauRx Therapeutics Ltd, TauRx Therapeutics Ltd. 3, Shenton Way, #21-04 Shenton House Singapore 068805 Republic of Singapore, and TauRx Research Facility Liberty Building Foresterhill Road Aberdeen AB25 2ZP United Kingdom
35.
Fatouros C, Pir GJ, Biernat J, Koushika SP, Mandelkow E, Mandelkow EM, Schmidt E, Baumeister R (2012) Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity. Hum Mol Genet 21:3587–3603, doi: 10.1093/hmg/dds190CrossRefPubMed
36.
Van Bebber F, Paquet D, Hruscha A, Schmid B, Haass C (2010) Methylene blue fails to inhibit Tau and polyglutamine protein dependent toxicity in zebrafish. Neurobiol Dis 39:265–271, doi:10.1016/j.nbd.2010.03.023 S0969-9961(10)00095-1CrossRefPubMed
37.
Deiana S, Harrington CR, Wischik CM, Riedel G (2009) Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology (Berl) 202:53–65, doi: 10.1007/s00213-008-1394-2CrossRef
38.
Medina DX, Caccamo A, Oddo S (2011) Methylene blue reduces abeta levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 21:140–149, doi:10.1111/j.1750-3639.2010.00430.x BPA430CrossRefPubMedCentralPubMed
39.
O’Leary JC 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J, Jones JR 3rd, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA (2010) Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 5:45, doi:10.1186/1750-1326-5-451750-1326-5-45CrossRefPubMedCentralPubMed
40.
Audet JN, Soucy G, Julien JP (2012) Methylene blue administration fails to confer neuroprotection in two amyotrophic lateral sclerosis mouse models. Neuroscience 209:136–143, doi: 10.1016/j.neuroscience.2011.12.047CrossRefPubMed
41.
Lougheed R, Turnbull J (2011) Lack of effect of methylene blue in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. PLoS One 6:e23141, doi:10.1371/journal.pone.0023141 PONE-D-10-05993CrossRefPubMedCentralPubMed
42.
Hosokawa M, Arai T, Masuda-Suzukake M, Nonaka T, Yamashita M, Akiyama H, Hasegawa M (2012) Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. PLoS One 7:e52389, doi: 10.1371/journal.pone.0052389CrossRefPubMedCentralPubMed
43.
Spires-Jones TL, Friedman T, Pitstick R, Polydoro M, Roe A, Carlson GA, Hyman BT (2014) Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy. Neurosci Lett 562C:63–68, doi: 10.1016/j.neulet.2014.01.013CrossRef
44.
Congdon EE, Wu JW, Myeku N, Figueroa YH, Herman M, Marinec PS, Gestwicki JE, Dickey CA, Yu WH, Duff KE (2012) Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 8:609-622. doi:10.4161/auto.1904819048
45.
Miyata Y, Rauch JN, Jinwal UK, Thompson AD, Srinivasan S, Dickey CA, Gestwicki JE (2012) Cysteine reactivity distinguishes redox sensing by the heat-inducible and constitutive forms of heat shock protein 70. Chem Biol 19:1391–1399, doi: 10.1016/j.chembiol.2012.07.026CrossRefPubMedCentralPubMed
46.
Buchholz K, Schirmer RH, Eubel JK, Akoachere MB, Dandekar T, Becker K, Gromer S (2008) Interactions of methylene blue with human disulfide reductases and their orthologues from Plasmodium falciparum. Antimicrob Agents Chemother 52:183–191, doi: 10.1128/AAC.00773-07CrossRefPubMedCentralPubMed
47.
Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER (1996) Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678–1683CrossRefPubMed
48.
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60, doi:0165-0270(84)90007-4CrossRefPubMed
49.
Jicha GA, Berenfeld B, Davies P (1999) Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer’s disease. J Neurosci Res 55:713–723CrossRefPubMed
50.
Hochgräfe K, Mandelkow EM (2013) Making the brain glow: in vivo bioluminescence imaging to study neurodegeneration. Mol Neurobiol 47:868–882, doi: 10.1007/s12035-012-8379-1CrossRefPubMed
51.
Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM (1999) Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry 38:3549–3558, doi: 10.1021/bi981874pCrossRefPubMed
52.
Oz M, Lorke DE, Hasan M, Petroianu GA (2011) Cellular and molecular actions of Methylene Blue in the nervous system. Med Res Rev 31:93–117, doi: 10.1002/med.20177CrossRefPubMedCentralPubMed
53.
Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM (2006) Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 281:1205–1214, doi:M507753200CrossRefPubMed
54.
Peter C, Hongwan D, Kupfer A, Lauterburg BH (2000) Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 56:247–250CrossRefPubMed
55.
Walter-Sack I, Rengelshausen J, Oberwittler H, Burhenne J, Mueller O, Meissner P, Mikus G (2009) High absolute bioavailability of methylene blue given as an aqueous oral formulation. Eur J Clin Pharmacol 65:179–189, doi: 10.1007/s00228-008-0563-xCrossRefPubMed
56.
57.
Mandelkow EM, Mandelkow E (1998) Tau in Alzheimer’s disease. Trends Cell Biol 8:425–427, doi:S0962-8924(98)01368-3CrossRefPubMed
58.
Thies E, Mandelkow EM (2007) Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci 27:2896–2907, doi: 10.1523/JNEUROSCI.4674-06.2007CrossRefPubMed
59.
Zempel H, Mandelkow E (2014) Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci 37:721–732, doi: 10.1016/j.tins.2014.08.004CrossRefPubMed
60.
Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D (2010) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081, doi: 10.1016/j.neuron.2010.11.030CrossRefPubMedCentralPubMed
61.
Von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E (2000) Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A 97:5129–5134, doi:97/10/5129CrossRef
62.
Stack C, Jainuddin S, Elipenahli C, Gerges M, Starkova N, Starkov AA, Jove M, Portero-Otin M, Launay N, Pujol A, Kaidery NA, Thomas B, Tampellini D, Beal MF, Dumont M (2014) Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet 23:3716–3732, doi: 10.1093/hmg/ddu080CrossRefPubMed
63.
Takeuchi H, Iba M, Inoue H, Higuchi M, Takao K, Tsukita K, Karatsu Y, Iwamoto Y, Miyakawa T, Suhara T, Trojanowski JQ, Lee VM, Takahashi R (2011) P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS One 6, e21050, doi: 10.1371/journal.pone.0021050CrossRefPubMedCentralPubMed
64.
Blennow K, Zetterberg H, Fagan AM (2012) Fluid biomarkers in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006221, doi: 10.1101/cshperspect.a006221CrossRefPubMedCentralPubMed
65.
66.
Wille H, Drewes G, Biernat J, Mandelkow EM, Mandelkow E (1992) Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro. J Cell Biol 118:573–584CrossRefPubMed
67.
Wang BJ, Pickhardt M, Mandelkow E, Mandelkow EM (2007) Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A 104:10252–10257, doi: 10.1073/pnas.0703676104CrossRefPubMedCentralPubMed
68.
Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E (2006) Global hairpin folding of tau in solution. Biochemistry 45:2283–2293, doi: 10.1021/bi0521543CrossRefPubMed
69.
Hochgräfe K, Sydow A, Mandelkow EM (2013) Regulatable transgenic mouse models of Alzheimer disease: onset, reversibility and spreading of Tau pathology. Febs J 280:4371–4381, doi: 10.1111/febs.12250CrossRefPubMed
70.
Ginimuge PR, Jyothi SD (2010) Methylene blue: revisited. J Anaesthesiol, Clin Pharmacol 26:517–520
71.
Akoury E, Pickhardt M, Gajda M, Biernat J, Mandelkow E, Zweckstetter M (2013) Mechanistic basis of phenothiazine-driven inhibition of Tau aggregation. Angew Chem Int Ed Engl 52:3511–3515, doi: 10.1002/anie.201208290CrossRefPubMed
72.
Crowe A, James MJ, Lee VM, Smith AB 3rd, Trojanowski JQ, Ballatore C, Brunden KR (2013) Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. J Biol Chem 288:11024–11037, doi: 10.1074/jbc.M112.436006CrossRefPubMedCentralPubMed
73.
Jinwal UK, Miyata Y, Koren J 3rd, Jones JR, Trotter JH, Chang L, O’Leary J, Morgan D, Lee DC, Shults CL, Rousaki A, Weeber EJ, Zuiderweg ER, Gestwicki JE, Dickey CA (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079–12088, doi: 10.1523/JNEUROSCI.3345-09.2009CrossRefPubMedCentralPubMed
74.
Bulic B, Pickhardt M, Mandelkow EM, Mandelkow E (2010) Tau protein and tau aggregation inhibitors. Neuropharmacology 59:276–289, doi:S0028-3908(10)00030-4CrossRefPubMed
75.
Chang E, Honson NS, Bandyopadhyay B, Funk KE, Jensen JR, Kim S, Naphade S, Kuret J (2009) Modulation and detection of tau aggregation with small-molecule ligands. Curr Alzheimer Res 6:409–414CrossRefPubMedCentralPubMed
76.
Brunden KR, Ballatore C, Crowe A, Smith AB 3rd, Lee VM, Trojanowski JQ (2010) Tau-directed drug discovery for Alzheimer’s disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 223:304–310, doi: 10.1016/j.expneurol.2009.08.031CrossRefPubMedCentralPubMed
77.
Bulic B, Pickhardt M, Khlistunova I, Biernat J, Mandelkow EM, Mandelkow E, Waldmann H (2007) Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem Int Ed Engl 46:9215–9219, doi: 10.1002/anie.200704051CrossRefPubMed
78.
Pickhardt M, Larbig G, Khlistunova I, Coksezen A, Meyer B, Mandelkow EM, Schmidt B, Mandelkow E (2007) Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tau aggregation and toxicity in vitro and in cells. Biochemistry 46:10016–10023, doi: 10.1021/bi700878gCrossRefPubMed
79.
Messing L, Decker JM, Joseph M, Mandelkow E, Mandelkow EM (2013) Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors. Neurobiol Aging 34:1343–1354, doi: 10.1016/j.neurobiolaging.2012.10.024CrossRefPubMed
80.
81.
Metcalf DJ, Garcia-Arencibia M, Hochfeld WE, Rubinsztein DC (2012) Autophagy and misfolded proteins in neurodegeneration. Exp Neurol 238:22–28, doi: 10.1016/j.expneurol.2010.11.003CrossRefPubMedCentralPubMed
82.
Wang M-VM, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170, doi: 10.1093/hmg/ddp367CrossRefPubMedCentralPubMed
83.
Cardenas-Aguayo MD, Gomez-Virgilio L, DeRosa S, Meraz-Rios MA (2014) The Role of Tau Oligomers in the Onset of Alzheimer’s Disease Neuropathology. ACS Chem Neurosci [Epub ahead of print]. doi:10.1021/cn500148z
84.
Riha PD, Bruchey AK, Echevarria DJ, Gonzalez-Lima F (2005) Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption. Eur J Pharmacol 511:151–158, doi: 10.1016/j.ejphar.2005.02.001CrossRefPubMed
85.
Bruchey AK, Gonzalez-Lima F (2008) Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol 3:72–79CrossRefPubMedCentralPubMed
86.
Mayer B, Brunner F, Schmidt K (1993) Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol 45:367–374CrossRefPubMed
87.
Jinwal UK, Groshev A, Zhang J, Grover A, Sutariya VB (2014) Preparation and characterization of methylene blue nanoparticles for Alzheimer’s disease and other tauopathies. Curr Drug Deliv 11:541–550CrossRefPubMed
Metadata
Title
Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau
Authors
Katja Hochgräfe
Astrid Sydow
Dorthe Matenia
Daniela Cadinu
Stefanie Könen
Olga Petrova
Marcus Pickhardt
Petra Goll
Fabio Morellini
Eckhard Mandelkow
Eva-Maria Mandelkow
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2015
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-015-0204-4

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