title: Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.
abstract: BACKGROUND
  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 Tau(ΔK)) or its repeat domain (TauRD-ΔK280, TauRD(ΔK)) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRD(ΔK) assembles into NFT concomitant with neuronal death, Tau(ΔK) 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 TauRD(ΔK) mice. Similarly, therapeutic MB treatment initiated after onset of cognitive impairments was ineffective in Tau(ΔK) mice. In contrast, preventive MB application starting before onset of functional deficits preserved cognition of Tau(ΔK) mice. Beside improved learning and memory, MB-treated Tau(ΔK) 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.
authors.affiliation: MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. hochgraefe@mpasmb.desy.de.
authors.forename: Katja
authors.initials: K
authors.lastname: Hochgräfe
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. sydow@mpasmb.desy.de.|MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. sydow@mpasmb.desy.de.
authors.forename: Astrid
authors.initials: A
authors.lastname: Sydow
authors.affiliation: MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. matenia@mpasmb.desy.de.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Matenia
authors.affiliation: MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. danielacadinu@gmail.com.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cadinu
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. stefanie.koenen@dzne.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Könen
authors.affiliation: MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. petrova@mpasmb.desy.de.
authors.forename: Olga
authors.initials: O
authors.lastname: Petrova
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. marcus.pickhardt@dzne.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Pickhardt
authors.affiliation: MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. petra.goll@t-online.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Goll
authors.affiliation: Center for Molecular Neurobiology Hamburg (ZMNH), Falkenried 94, 20251, Hamburg, Germany. morellini.fabio@zmnh.uni-hamburg.de.
authors.forename: Fabio
authors.initials: F
authors.lastname: Morellini
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mand@mpasmb.desy.de.|CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mand@mpasmb.desy.de.|MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. mand@mpasmb.desy.de.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: DZNE (German Center for Neurodegenerative Diseases), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mandelkow@dzne.de.|CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. mandelkow@dzne.de.|MPI for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestr. 85, 22607, Hamburg, Germany. mandelkow@dzne.de.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008751:Methylene Blue / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024801:Tauopathies / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D013997:Time Factors; D016896:Treatment Outcome; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; D008751:Methylene Blue