Top

Published in:

Open Access 01-11-2015 | Original Paper

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies

Authors: Jens Wagner, Sybille Krauss, Song Shi, Sergey Ryazanov, Julia Steffen, Carolin Miklitz, Andrei Leonov, Alexander Kleinknecht, Bettina Göricke, Jochen H. Weishaupt, Daniel Weckbecker, Anne M. Reiner, Wolfgang Zinth, Johannes Levin, Dan Ehninger, Stefan Remy, Hans A. Kretzschmar, Christian Griesinger, Armin Giese, Martin Fuhrmann

Published in: Acta Neuropathologica | Issue 5/2015

Abstract

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.

Available only for authorised users

Akoury E, Pickhardt M, Gajda M, Biernat J, Mandelkow E, Zweckstetter M (2013) Mechanistic basis of phenothiazine-driven inhibition of Tau aggregation. Angew Chem 52:3511–3515. doi:10.1002/anie.201208290 CrossRef

Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42:631–639CrossRefPubMed

Bader B, Nubling G, Mehle A, Nobile S, Kretzschmar H, Giese A (2011) Single particle analysis of tau oligomer formation induced by metal ions and organic solvents. Biochem Biophys Res Commun 411:190–196. doi:10.1016/j.bbrc.2011.06.135 CrossRefPubMed

Ballatore C, Brunden KR, Piscitelli F et al (2010) Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation. J Med Chem 53:3739–3747. doi:10.1021/jm100138f PubMedCentralCrossRefPubMed

Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG (2004) Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 165:1643–1652. doi:10.1016/S0002-9440(10)63421-9 PubMedCentralCrossRefPubMed

Berger Z, Roder H, Hanna A et al (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci Off J Soc Neurosci 27:3650–3662. doi:10.1523/JNEUROSCI.0587-07.2007 CrossRef

Bevins RA, Besheer J (2006) Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat Protoc 1:1306–1311. doi:10.1038/nprot.2006.205 CrossRefPubMed

Bieschke J, Giese A, Schulz-Schaeffer W et al (2000) Ultrasensitive detection of pathological prion protein aggregates by dual-color scanning for intensely fluorescent targets. Proc Natl Acad Sci USA 97:5468–5473PubMedCentralCrossRefPubMed

Boutajangout A, Quartermain D, Sigurdsson EM (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci Off J Soc Neurosci 30:16559–16566. doi:10.1523/JNEUROSCI.4363-10.2010 CrossRef

10.

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259CrossRefPubMed

11.

Brunden KR, Zhang B, Carroll J et al (2010) Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci Off J Soc Neurosci 30:13861–13866. doi:10.1523/JNEUROSCI.3059-10.2010 CrossRef

12.

Bugiani O, Murrell JR, Giaccone G et al (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 58:667–677CrossRefPubMed

13.

Bulic B, Pickhardt M, Khlistunova I et al (2007) Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem 46:9215–9219. doi:10.1002/anie.200704051 CrossRef

14.

Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Kayed R (2014) Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis 40(Suppl 1):S97–S111. doi:10.3233/JAD-132477 PubMed

15.

Chai X, Wu S, Murray TK et al (2011) Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem 286:34457–34467. doi:10.1074/jbc.M111.229633 PubMedCentralCrossRefPubMed

16.

Congdon EE, Wu JW, Myeku N et al (2012) Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 8:609–622. doi:10.4161/auto.19048 PubMedCentralCrossRefPubMed

17.

Giacobini E, Gold G (2013) Alzheimer disease therapy—moving from amyloid-beta to tau. Nat Rev Neurol 9:677–686. doi:10.1038/nrneurol.2013.223 CrossRefPubMed

18.

Giannakopoulos P, Herrmann FR, Bussiere T et al (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60:1495–1500CrossRefPubMed

19.

Giese A, Levin J, Bertsch U, Kretzschmar H (2004) Effect of metal ions on de novo aggregation of full-length prion protein. Biochem Biophys Res Commun 320:1240–1246. doi:10.1016/j.bbrc.2004.06.075 CrossRefPubMed

20.

Gillman PK (2011) CNS toxicity involving methylene blue: the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity. J Psychopharmacol 25:429–436. doi:10.1177/0269881109359098 CrossRefPubMed

21.

Goedert M, Jakes R, Vanmechelen E (1995) Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neurosci Lett 189:167–169CrossRefPubMed

22.

Gogolla N, Galimberti I, DePaola V, Caroni P (2006) Staining protocol for organotypic hippocampal slice cultures. Nat Protoc 1:2452–2456. doi:10.1038/nprot.2006.180 CrossRefPubMed

23.

Gomez-Isla T, Hollister R, West H et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24. doi:10.1002/ana.410410106 CrossRefPubMed

24.

Hosokawa M, Arai T, Masuda-Suzukake M et al (2012) Methylene blue reduced abnormal tau accumulation in P301L tau transgenic mice. PLoS One 7:e52389. doi:10.1371/journal.pone.0052389 PubMedCentralCrossRefPubMed

25.

Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222. doi:10.1016/j.cell.2012.02.040 PubMedCentralCrossRefPubMed

26.

Ishizawa K, Dickson DW (2001) Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol 60:647–657PubMed

27.

Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132CrossRefPubMed

28.

Kersaitis C, Halliday GM, Kril JJ (2004) Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies. Acta Neuropathol 108:515–523. doi:10.1007/s00401-004-0917-0 CrossRefPubMed

29.

Khlistunova I, Biernat J, Wang Y et al (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:10.1074/jbc.M507753200 CrossRefPubMed

30.

Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. doi:10.1146/annurev.neuro.24.1.1121 CrossRefPubMed

31.

Lee VM, Brunden KR, Hutton M, Trojanowski JQ (2011) Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med 1:a006437. doi:10.1101/cshperspect.a006437 PubMedCentralCrossRefPubMed

32.

Lossos A, Reches A, Gal A et al (2003) Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family. J Neurol 250:733–740. doi:10.1007/s00415-003-1074-4 CrossRefPubMed

33.

Masliah E (2001) Recent advances in the understanding of the role of synaptic proteins in Alzheimer’s disease and other neurodegenerative disorders. J Alzheimers Dis 3:121–129PubMed

34.

Masuda M, Suzuki N, Taniguchi S et al (2006) Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 45:6085–6094. doi:10.1021/bi0600749 CrossRefPubMed

35.

Nubling G, Bader B, Levin J, Hildebrandt J, Kretzschmar H, Giese A (2012) Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with alpha-synuclein at the single molecule level. Mol Neurodegener 7:35. doi:10.1186/1750-1326-7-35 PubMedCentralCrossRefPubMed

36.

O’Leary JC 3rd, Li Q, Marinec P et al (2010) Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 5:45. doi:10.1186/1750-1326-5-45 PubMedCentralCrossRefPubMed

37.

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.20177 PubMedCentralCrossRefPubMed

38.

Pickhardt M, Gazova Z, von Bergen M et al (2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer’s paired helical filaments in vitro and in cells. J Biol Chem 280:3628–3635. doi:10.1074/jbc.M410984200 CrossRefPubMed

39.

Pickhardt M, Larbig G, Khlistunova I et al (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/bi700878g CrossRefPubMed

40.

Polydoro M, Acker CM, Duff K, Castillo PE, Davies P (2009) Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci Off J Soc Neurosci 29:10741–10749. doi:10.1523/JNEUROSCI.1065-09.2009 CrossRef

41.

Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481. doi:10.1126/science.1113694 PubMedCentralCrossRefPubMed

42.

Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain J Neurol 135:2169–2177. doi:10.1093/brain/aws143 CrossRef

43.

Sperfeld AD, Collatz MB, Baier H et al (1999) FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol 46:708–715CrossRefPubMed

44.

Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622. doi:10.1016/S1474-4422(13)70090-5 CrossRefPubMed

45.

Terwel D, Lasrado R, Snauwaert J et al (2005) Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem 280:3963–3973. doi:10.1074/jbc.M409876200 CrossRefPubMed

46.

Togo T, Dickson DW (2002) Tau accumulation in astrocytes in progressive supranuclear palsy is a degenerative rather than a reactive process. Acta Neuropathol 104:398–402. doi:10.1007/s00401-002-0569-x CrossRefPubMed

47.

Wagner J, Ryazanov S, Leonov A et al (2013) Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol 125:795–813. doi:10.1007/s00401-013-1114-9 PubMedCentralCrossRefPubMed

48.

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 USA 93:11213–11218PubMedCentralCrossRefPubMed

49.

Yanamandra K, Kfoury N, Jiang H et al (2013) Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80:402–414. doi:10.1016/j.neuron.2013.07.046 PubMedCentralCrossRefPubMed

50.

Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351. doi:10.1016/j.neuron.2007.01.010 CrossRefPubMed

51.

Zhang B, Carroll J, Trojanowski JQ et al (2012) 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 Off J Soc Neurosci 32:3601–3611. doi:10.1523/JNEUROSCI.4922-11.2012 CrossRef

Title: Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies
Authors: Jens Wagner
Sybille Krauss
Song Shi
Sergey Ryazanov
Julia Steffen
Carolin Miklitz
Andrei Leonov
Alexander Kleinknecht
Bettina Göricke
Jochen H. Weishaupt
Daniel Weckbecker
Anne M. Reiner
Wolfgang Zinth
Johannes Levin
Dan Ehninger
Stefan Remy
Hans A. Kretzschmar
Christian Griesinger
Armin Giese
Martin Fuhrmann
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1483-3

At a glance: The STEP trials

Springer Medicine

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2015

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury

Rab1-dependent ER–Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS

PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia

Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models

Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies