FTDP-17-typische frontale Verhaltensänderungen bei R406W-Tau transgenen Mäusen

Although research in neurodegererative disease has made remarkable progress in the last couple of years, there is still a lack of therapeutic possibilities for Alzheimer´s and Parkinson´s disease and Fronto-temporal dementia. The increasing number of patients is a challenge for health systems worldwide. In Fronto-temporal dementia (FTD), the progressing cerebral degeneration mostly affects the frontal and temporal lobe of the brain. Because of that, affected patients do clinically not present deficits in memory and orientation in the first place, they rather develop a progressing alteration in personality, activity and social attitude. This leads to a considerable impairment in social interaction. Most cases of FTD are sporadic but 20-30% are heriditary. Most of these cases are caused by Tau-gene mutations on chromosome 17q21, which lead to the name Fronto-temporal dementia with parkinson associated with chromosome 17 (FTDP-17). Protein tau is a microtuble associated protein and is essential for microtuble assembly in cell division and the axonal transport. In FTDP-17, Tau is hyperphosphorylated which leads to an impairment between Tau protein and the microtubles and to intracellular deposits which are called neurofibrillary tangles. The development of qualified animal models is important to understand the pathophysiological principles of FTDP-17. There is still a lack of information about behavioural alterations of these mouse models. The aim of this study was to compare two transgenic mouse-models (hWt, human wild-type-Tau and RW, human Tau with R406W-mutation) and one non-transgenic control group (WT, wild-type-Tau) using five different behavioural tests (OFT, ORT, Rota-ROD, FST and SIT) to investigate common behavioural alterations occurring in FTDP-17 affected individuals (disinhibition, social withdrawal, memory deficit, akinetic-rigid-syndrome, depression). Nearly all behavioural tests showed an increased locomotoric activity of the RW-mice at nearly every time point: A better performance in the OFT for all investigated parameters (track-length, velocity and activity, more movement through the center of the field), a better performance on the Rota-ROD, less floating and more swimming in the FST and an increased number of social contacts in the SIT (at the time points one and two) of the RW-mice compared to the WT- and the hWT-mice suggest a disinhibition of the RW-mice. In contrast to the frontal disinhibition of the RW-mice with an increased number of social contacts at the first two time points, the RW-mice showed significantly less social contacts with increasing age, suggesting an tendency to social withdrawal. Neither the RW-mice nor the hWT-mice showed signs of depression during the course of the experiments. They did not show motoric deficits suggesting an acinetic-rigid Parkinson-syndrome either. On the contrary, the RW-mice showed a remarkably better motoric performance than the hWT- and WT-mice. This surprisingly suggests an increased motoric functionality and psychomotoric activity due to the overexpression of human mutated Tau-protein in the early course of the disease. Both transgenic mouse-models showed no signs of memory deficits in the ORT suggesting that there is no negative effect of the human Tau protein on the memory function of the mice. In conclusion it was possible to show behavioural alterations associated with FTDP-17, especially frontal disinhibition of the RW-mice. Because the behavioural pathologies can be quantified and are reproducible, the behavioural pathology can e.g. be used as a measure of effectivity of an therapy using the OFT, FST and SIT.