2. Academic Validation
  3. Piericidin A aggravates Tau pathology in P301S transgenic mice

Piericidin A aggravates Tau pathology in P301S transgenic mice

  • PLoS One. 2014 Dec 1;9(12):e113557. doi: 10.1371/journal.pone.0113557.
Matthias Höllerhage 1,  Roman Deck 2,  Anderson De Andrade 3,  Gesine Respondek 1,  Hong Xu 3,  Thomas W Rösler 3,  Mohamed Salama 4,  Thomas Carlsson 5,  Elizabeth S Yamada 6,  Seham A Gad El Hak 7,  Michel Goedert 8,  Wolfgang H Oertel 2,  Günter U Höglinger 1
Affiliations

Affiliations

  • 1 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.
  • 2 Dept. of Neurology, Philipps-Universität, Marburg, Germany.
  • 3 Dept. of Neurology, Philipps-Universität, Marburg, Germany; German Center for Neurodegenerative Diseases, Dept. for Translational Neurodegeneration, Munich, Germany.
  • 4 Dept. of Neurology, Philipps-Universität, Marburg, Germany; Department of Toxicology, Mansoura University, Mansoura, Egypt.
  • 5 Dept. of Neurology, Philipps-Universität, Marburg, Germany; Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 6 Dept. of Neurology, Philipps-Universität, Marburg, Germany; Experimental Neuropathology Laboratory, Federal University of Pará, Belém, Brazil.
  • 7 Department of Toxicology, Mansoura University, Mansoura, Egypt.
  • 8 Division of Neurobiology, University of Cambridge, Cambridge, United Kingdom.
PMID: 25437199 DOI: 10.1371/journal.pone.0113557
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.

Discussion: 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.

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