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@ARTICLE{Hllerhage:137713,
author = {Höllerhage, Matthias and Deck, Roman and De Andrade,
Anderson and Respondek, Gesine and Xu, Hong and Rösler,
Thomas W and Salama, Mohamed and Carlsson, Thomas and
Yamada, Elizabeth S and Gad El Hak, Seham A and Goedert,
Michel and Oertel, Wolfgang H and Höglinger, Günter U},
title = {{P}iericidin {A} aggravates {T}au pathology in {P}301{S}
transgenic mice.},
journal = {PLOS ONE},
volume = {9},
number = {12},
issn = {1932-6203},
address = {San Francisco, California, US},
publisher = {PLOS},
reportid = {DZNE-2020-04035},
pages = {e113557},
year = {2014},
abstract = {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.},
keywords = {Animals / Cerebral Cortex: drug effects / Cerebral Cortex:
pathology / Exons: genetics / Gene-Environment Interaction /
Humans / Mice / Mice, Transgenic / Mutation /
Phosphorylation: drug effects / Pyridines: toxicity /
Synapses: drug effects / Synapses: pathology / Tauopathies:
genetics / Tauopathies: metabolism / Tauopathies: pathology
/ tau Proteins: genetics / tau Proteins: metabolism /
Pyridines (NLM Chemicals) / tau Proteins (NLM Chemicals) /
piericidin A (NLM Chemicals)},
cin = {AG Höglinger 1},
ddc = {610},
cid = {I:(DE-2719)1110002},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25437199},
pmc = {pmc:PMC4249965},
doi = {10.1371/journal.pone.0113557},
url = {https://pub.dzne.de/record/137713},
}