Verhaltensanalyse bei Tau-transgenen Mäusen unter Intoxikation mit Saft aus Annona muricata

Tauopathies are a group of neurodegenerative diseases characterized by pathological changes in the Tau protein in the sense of dysfunction and accumulation. As a microtubule-associated protein in the central nervous system, Tau plays an important role in the maintenance of cell shape and structure, axonal transport of intracellular components, and growth and stabilization of axons during neuronal development. Both mutations and environmental factors can cause a pathological change in the Tau protein. A number of point mutations in the Tau gene are associated with frontotemporal lobar degeneration with Tau deposits. The neurotoxin annonacin contained in plants of the Annonaceae family is a potent complex-I inhibitor of the respiratory chain of the mitochondria and is considered to be the cause of the atypical Parkinson's syndromes in Guadeloupe, which are classified as tauopathies. An interaction between genetic and environmental factors in pathological alterations of the Tau protein was demonstrated in advance of the present study by a parenteral annonacin infusion into transgenic mice with mutated human Tau gene with the point mutation R406W, which causes the exchange of an amino acid arginine for tryptophan. The short-term exposure to annonacin increased the dysfunction and accumulation of the Tau protein in the transgenic mice in vivo. The aim of this work was to analyze the long-term effects of both factors under physiological conditions by enteral administration of fruit juice from Annona (A.) muricata, a major representative of the Annonaceae plant family, in a mouse model. To this end, the behavioral characteristics of two transgenic mouse lines expressing human Wild-type Tau (hWT) or human R406W Tau and a non-transgenic control group (nTg) were investigated during intoxication with fruit juice from A. muricata for one year. The results were compared with the results of a behavioral analysis of genetically identical mouse lines without the administration of juice from A. muricata. The behavioral tests should provide information on whether the mouse models show phenotypic characteristics of a genetically determined tauopathy (e.g. Frontotemporal lobar degeneration with Tau deposits associated with Tau mutations). Further, it should be clarified whether non-transgenic mice develop clinical characteristics of atypical Parkinson's syndromes of Guadeloupe by the administration of juice from A. muricata. In addition, it was investigated whether environmental exposure to the juice from A. muricata enhances the behavioral traits of Tau-transgenic mice. The behavioral traits of the test animals were examined by means of five behavioral tests at five points in time. The Rotarod Test (ROD) examined motor functions and coordination. The Open Field Test (OFT) analyzed locomotor activity and exploratory behavior and detected potential anxious behavior. The Object Recognition Test (ORT) tested the declarative memory. The Social Interaction Test (SIT) was used to identify the disinhibition of social behavior or social withdrawal. The Forced Swimming Test (FST) revealed a possible depressive behavior of the test animals. The increased locomotor activity and exploratory behavior of the transgenic R406W mice demonstrated in the behavioral tests corresponds to the psychopathological characteristics of a genetic tauopathy in terms of psychomotor disinhibition or loss of frontal inhibition. The increasing change in affective and anxiety-related behavior of the mice with the duration of treatment with juice from A. muricata (increased depressive behavior, increased anxiety) are also observed in the atypical Parkinson's syndrome of Guadeloupe, which is associated with the consumption of A. muricata products. Limitations of declarative memory did not occur in the mice during the investigated period. However, the loss of the habituation of the R406W genotype with regard to locomotor activity may indicate a disruption of learning behavior and discrete memory deficits. Motor impairment did not occur in any genotype in any treatment arm, possibly due to the limited observation period of 12 months. In the literature, such deficits in the R406W mouse model used in the present study (same Tau isoform, same promoter) were only detected at an older age of the test animals. In various tests, the Tau-transgenic animals showed enhanced pathological behavioral traits when treated with juice from A. muricata, suggesting an interaction of genetic predisposition and environmental influence. For example, the transgenic R406W animals treated with juice from A. muricatashowed reduced erection behavior despite the increased locomotor activity, and hWT animals covered in the OFT a shorter distance at a slower speed than water-treated animals of the same genotype. The results of this work confirm the findings of earlier in vitro and in vivo studies. Due to the toxic effects of annonacin on the central nervous system, the consumption of fruits and juice from A. muricata should be avoided. Considering that malfunctions and pathological deposits of the Tau protein play a major role in neurodegenerative Alzheimer's disease, therapies targeting the Tau protein are of considerable scientific interest, especially after the failure of various therapeutic approaches against beta-amyloid. In this context, mouse models can show correlations between the Tau-mediated pathological event and neurodegeneration in vivo. Therapeutic approaches, which focus on pathological changes caused by the Tau protein, can be tested for effectiveness and tolerability in Tau-transgenic mouse models using behavioral analysis.