title: Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice.
abstract: Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany; Experimental Neuropathology Laboratory, University Hospital João de Barros Barreto, Federal University of Pará, 66073-000 Belém, Brazil.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Yamada
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), D-81677 Munich, Germany; Department of Neurology, Technical University Munich, D-81377 Munich, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Respondek
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Müssner
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), D-81677 Munich, Germany; Department of Neurology, Technical University Munich, D-81377 Munich, Germany.
authors.forename: Anderson
authors.initials: A
authors.lastname: de Andrade
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), D-81677 Munich, Germany; Department of Neurology, Technical University Munich, D-81377 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.affiliation: INSERM, Unité 679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75013 Paris, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: INSERM, Unité 679, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75013 Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rastetter
authors.affiliation: Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Tarze
authors.affiliation: Laboratoire de Biologie Cellulaire du Vieillissement, UR4-IFR83, Université Pierre et Marie Curie-Paris 6, 4 place Jussieu, 75252 Paris Cedex 05, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salama
authors.affiliation: Laboratoire de Pharmacognosie, CNRS UMR 8076 BioCIS, Labex LERMIT, Faculté de Pharmacie, Université Paris-Sud, 92296 Châtenay-Malabry, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Champy
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: Experimental Neurology, Philipps University, D-35037 Marburg, Germany; German Center for Neurodegenerative Diseases (DZNE), D-81677 Munich, Germany; Department of Neurology, Technical University Munich, D-81377 Munich, Germany. Electronic address: guenter.hoeglinger@dzne.de.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000818:Animals; D001120:Arginine / Q000235:genetics; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009026:Mortality; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D014364:Tryptophan / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; C053442:annonacin; D014364:Tryptophan; D001120:Arginine
keywords: Environmental neurotoxin; Microtubule-associated protein tau; Neurodegeneration; Tauopathy