TY  - JOUR
AU  - Höllerhage, Matthias
AU  - Deck, Roman
AU  - De Andrade, Anderson
AU  - Respondek, Gesine
AU  - Xu, Hong
AU  - Rösler, Thomas W
AU  - Salama, Mohamed
AU  - Carlsson, Thomas
AU  - Yamada, Elizabeth S
AU  - Gad El Hak, Seham A
AU  - Goedert, Michel
AU  - Oertel, Wolfgang H
AU  - Höglinger, Günter U
TI  - Piericidin A aggravates Tau pathology in P301S transgenic mice.
JO  - PLOS ONE
VL  - 9
IS  - 12
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-04035
SP  - e113557
PY  - 2014
AB  - 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.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.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.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.
KW  - Animals
KW  - Cerebral Cortex: drug effects
KW  - Cerebral Cortex: pathology
KW  - Exons: genetics
KW  - Gene-Environment Interaction
KW  - Humans
KW  - Mice
KW  - Mice, Transgenic
KW  - Mutation
KW  - Phosphorylation: drug effects
KW  - Pyridines: toxicity
KW  - Synapses: drug effects
KW  - Synapses: pathology
KW  - Tauopathies: genetics
KW  - Tauopathies: metabolism
KW  - Tauopathies: pathology
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Pyridines (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - piericidin A (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25437199
C2  - pmc:PMC4249965
DO  - DOI:10.1371/journal.pone.0113557
UR  - https://pub.dzne.de/record/137713
ER  -