Oertel is Senior research Professor of the Charitable Hertie Foundation, Frankfurt/Main, Germany

Oertel is Senior research Professor of the Charitable Hertie Foundation, Frankfurt/Main, Germany. N = 9 wild-type mice) at a dose of 0.5 mg/kg/d for a CGP 36742 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 CGP 36742 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. == Introduction == Tau is a predominantly neuronal protein of which six major isoforms are generated by alternative splicing[1][4]from one geneMAPT, localized on the long arm of chromosome 17 (17q21)[5]. Tau is involved in the assembly and stabilization of microtubules[6]. Thus it plays an important CGP 36742 role in axonal transport and neuronal viability. Intracellular aggregation of hyperphosphorylated tau protein is the histopathological hallmark of a group of neurodegenerative diseases, called tauopathies[7],[8]. The pathological hyperphosphorylation of tau-protein is considered as a possible early step in the formation of tau-aggregates in tauopathies[9]. The etiology of neurodegenerative tauopathies is multifactorial. MonogeneticMAPTmutations are responsible for some hereditary tauopathies, where so far, 51 disease-causingMAPTmutations are known[4]. One of these is the P301S mutation in exon 10, which leads to a substitution of the proline at position 301 by serine. The P301S mutation was first described in 1999 in families showing symptoms of corticobasal degeneration and frontotemporal dementia[10],[11]. Further work demonstrated, that there are two predominant clinical phenotypes in the patients carrying this mutation. Some show mainly parkinsonism similar to patients with progressive supranuclear palsy (PSP), while others show mainly symptoms of frontotemporal dementia[12]. This observation strongly suggests that independent genetic or environmental factors appear to shape the clinical phenotype of the disease caused by the P301SMAPTmutation. In contrast to the purely genetically caused tauopathies described above, there are other tauopathies that appear to originate from exposure to a specific environmental factor. One prototypic example is the atypical Parkinson syndrome with tau pathology on the Caribbean island of Guadeloupe. Epidemiological studies have linked the disease to a high consumption of products from Annonaceae plants[13][15]. These plants contain high amounts of acetogenins, a class of lipophilic and potent inhibitors of complex I of the mitochondrial respiratory chain[16],[17]. The major representative of the annonaceous acetogenins is annonacin[18]. Systemic exposure to annonacin for 28 days induced neurodegeneration in ratsin vivo[19]. Treatment of cultured striatal CD19 neurons from embryonic rats led to the accumulation of hyperphosphorylated tau in the cell soma of these cells[20]. These data strongly suggest that an environmental factor can trigger a tauopathy. Between these two extremes of tauopathies, with solely monogenetic or environmental causes, the vast majority of sporadic cases are considered to result from an interaction CGP 36742 of genetic predispositions (e.g.[21]) and environmental triggers or modifiers. However, not much is known about environmental factors that could either trigger or modify the course of a genetically determined tauopathy. Since the consumption of products from Annonaceae plants is uncommon in North America or Europe, the question arises, which other environmental factors could be relevant in the etiology of tauopathies. A previousin vitrostudy showed, that a broad spectrum of natural complex I inhibitors can induce tau pathology and cell death in cultured neurons[22]. One of the most potent natural neurotoxins to induce somatodendritic accumulation of phosphorylated tau and cell death in nanomolar concentrations is piericidin A[22]. Piericidin A, is the most common member of the family of piericidins, a class of potent complex I inhibitors synthesized bystreptomyces spp.[23],[24]. These bacteria are ubiquitously present in marine and agricultural habitats[25]. The present study aimed to investigate the potential of piericidin A to trigger a tauopathyin vivoin wild type mice or to modify the course of a genetically caused tauopathy in transgenic mice overexpressing human P301S mutant tau[26]. Therefore, we treated P301S tau transgenic mice and wild-type mice with Piericidin A or vehicle by CGP 36742 subcutaneous infusion over a period of 28 days and analyzed their brains for the presence and severity of tau-pathology. == Methods == == Animals == P301S transgenic mice were developed by.