Der chronische Konsum von Fruchtsaft aus Annona muricata initiiert und beschleunigt die Entwicklung einer Tauopathie in Wildtyp und MAPT transgenen Mäusen

Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by the accumulation of the microtubule-stabilizing protein tau in various brain regions. Frontotemporal dementia with parkinsonism linked to chromosome 17 associated with mutations in the microtubule-associated protein tau (FTDP-17 MAPT) and progressive supranuclear palsy (PSP) are representatives of this disease class and while FTDP-17 MAPT is linked to mutations in the tau gene, the aetiology of PSP remains unknown. Insights into the pathogenesis of PSP were gained by the observation that the high prevalence of atypical parkinsonian syndromes on Guadeloupe was linked to high consumption of products made of Annona muricata (Spanish: Guanábana, Portuguese: Graviola). In fruits and derived products of this species Annonacin, a potent and lipophilic inhibitor of complex I of the respiratory chain, could be isolated. Annonacin was shown to cause ATP depletion and somatodendritic tau redistribution with accumulation of hyperphosphorylated tau in the central nervous system. To elucidate the interaction of environmental and genetic factors that contribute to the development of tau pathology, the present work studied two transgenic mouse lines expressing the R406W mutated human tau protein or non-mutated human wild type tau (hWT) versus control animals (nTg). Over the period of one year mice either received Graviola, a tropical fruit juice made of Annona muricata or water. Afterwards, mice were sacrificed and brains were immunohistochemically studied followed by stereologic evaluation of total cell counts. In frontal- and parietal cortices the total cell counts of neurons reactive at the 231 (AT180, p<0.001) and 202/205 (AT8, p<0.05) epitopes of the tau protein were significantly higher in mice treated with juice. The staining with the AT180 antibody revealed the highest number of phospho-tau positive neurons in mice carrying the R406W mutation from the juice group when compared with their water drinking littermates (frontal cortex: 79893±8046 vs 50628±4938, p<0.05; parietal cortex: 26396±1547 vs 19943±2313, p<0.01). In addition, the staining of apical dendrites was reduced in R406W mice of the juice group. Similar results were found for the AT8-reactive epitopes 202/205. In R406W mice all investigated subregions of hippocampus, including hilus, CA1 and CA2/3, demonstrated the same differences between treatment modalities. Furthermore, also juice treated mice carrying non-mutated human wild type tau exhibited staining by the AT8 antibody and in frontal- and parietal cortices also non-transgenic mice were found to be tau-positive. Moreover, while the AD2-reactive epitopes 396/404 were completely negative in the water treated group as well as in hWT and non-transgenic mice treated with Annona muricata, it was detected in neurons of juice treated R406W mice. No neuronal cell loss was observed, and also the number of microglia and astrocytes was unchanged. Nevertheless, the optical synaptophysin density in frontal cortex of juice drinking mice was significantly lower, which can be considered an early step in the neurodegenerative process. In addition, an increase in the number of 3-nitrotyrosine-reactive neurons was observed upon chronic juice consumption, suggesting the generation of reactive nitrogen species. In conclusion, the results of the present study demonstrate an additive effect between an environmental factor and a genetic mutation in the development of tau hyperphosphorylation. Chronic oral consumption of juice made of Annona muricata over the period of one year provoked accumulation of hyperphosphorylated tau as well as somatodendritic tau redistribution in R406W mutant mice. Furthermore, the tau hyperphosphorylation found in mice carrying non-mutated human wild-type tau was comparable to findings made in patients suffering from guadeloupean parkinsonism. In the light of these results the consumption of Annona muricata juice should be avoided.