title: Piericidin A aggravates Tau pathology in P301S transgenic mice.
abstract: OBJECTIVE
  The P301S mutation in exon 10 of the tau gene causes a hereditary tauopathy. While mitochondrial complex I inhibition has been linked to sporadic tauopathies. Piericidin A is a prototypical member of the group of the piericidins, a class of biologically active natural complex I inhibitors, isolated from streptomyces spp. with global distribution in marine and agricultural habitats. The aim of this study was to determine whether there is a pathogenic interaction of the environmental toxin piericidin A and the P301S mutation.
  
  
  METHODS
  Transgenic mice expressing human tau with the P301S-mutation (P301S+/+) and wild-type mice at 12 weeks of age were treated subcutaneously with vehicle (N = 10 P301S+/+, N = 7 wild-type) or piericidin A (N = 9 P301S+/+, N = 9 wild-type mice) at a dose of 0.5 mg/kg/d for a period of 28 days via osmotic minipumps. Tau pathology was measured by stereological counts of cells immunoreative with antibodies against phosphorylated tau (AD2, AT8, AT180, and AT100) and corresponding Western blot analysis.
  
  
  RESULTS
  Piericidin A significantly increased the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S+/+ mice, but only to a variable and mild extent in wild-type mice. Furthermore, piericidin A led to increased levels of pathologically phosphorylated tau only in P301S+/+ mice. While we observed no apparent cell loss in the frontal cortex, the synaptic density was reduced by piericidin A treatment in P301S+/+ mice.
  
  
  CONCLUSIONS
  This study shows that exposure to piericidin A aggravates the course of genetically determined tau pathology, providing experimental support for the concept of gene-environment interaction in the etiology of tauopathies.
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany; Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Deck
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany.
authors.forename: Anderson
authors.initials: A
authors.lastname: De Andrade
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany; Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Respondek
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rösler
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; Department of Toxicology, Mansoura University, Mansoura, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salama
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carlsson
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; Experimental Neuropathology Laboratory, Federal University of Pará, Belém, Brazil.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Yamada
authors.affiliation: Department of Toxicology, Mansoura University, Mansoura, Egypt.
authors.forename: Seham A
authors.initials: SA
authors.lastname: Gad El Hak
authors.affiliation: Division of Neurobiology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.affiliation: Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany; Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D005091:Exons / Q000235:genetics; D059647:Gene-Environment Interaction; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D011725:Pyridines; D016875:tau Proteins; C100213:piericidin A