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Abstract:

Neuropathological hallmarks of Alzheimer’s disease (AD) include brain β-amyloid deposition and neurofibrillary tau-tangles, but progressive cognitive deterioration essentially characterizes this disorder at the behavioural level. Genetically modified mice are important research models for the study of pathogenic mechanisms of AD, and for the elucidation of therapeutic strategies. Therefore, two transgenic mouse strains were generated, based on the inducible expression (tet-off system) of the four-repeat domain of human tau protein carrying the FTDP-17 mutation ΔK280 (TauRD/ΔK280), or the ΔK280 plus two proline mutations in the hexapeptide motifs (TauRD/ΔK280/I277P/I308P) (Mocanu et al., 2008). The ΔK280 mutation accelerates aggregation (pro-aggregation mutant; PRO), whereas the proline mutations inhibit tau aggregation in vitro and in cell models (anti-aggregation mutant; ANTI). The PRO-aggregation mice show prominent neurofibrillary tangles and neuronal loss in the hippocampus from 3 months onwards, whereas the ANTI mice are spared (Fig. 1). These two strains were compared with nontransgenic littermates (control animals; CTRL) in a behavioral test battery. The test battery included neuromotor tests (grip strength, rotarod, and cage activity), exploratory tests (open field and social exploration), and learning and memory tests (passive avoidance task and Morris water maze). Moreover neuroplasticity in area-CA1 of hippocampal slices derived from these same mice was measured by short and long-term plasticity. Short term plasticity consisted of paired-pulse stimulation (2 pulses in rapid succession with different interpulse intervals). Whilst long term plasticity was measured in the form of long term potentiation (LTP) a cellular correlate of learning and memory, using a single theta-burst stimulation. Results show that the PRO mice were impaired in the single trial retention test (Fig. 2), and these mice were inferior in learning the Morris water maze compared with ANTI and CTRL mice. PRO mice found the platform slower and had longer swimming paths than CTRL and ANTI mice on the 2nd and 3rd day of acquisition (Fig. 3). All 3 groups had normal sensorimotor function, highlighting the specificity of the memory deficit. Furthermore, the PRO mice showed a deficiency in hippocampal synaptic plasticity, as assessed by LTP and paired-pulse measurements (Fig 4). After testing of the behavior and LTP the remaining PRO mice were divided into two groups. In one of these, the expression of tau was switched off by doxycycline for 3 months, the other group continued to express the tau transgene. When expression of tau was switched off a cognitive improvement was observed for PRO mice. In the Morris water maze test with the platform placed in another position (transfer training), we found that PRO mice that received doxycycline, acquired the new position at control level, whereas PRO mice that had continued to express tau protein were much worse at this task (Fig. 5). Additional analyses revealed that these mice used another search strategy, e.g. perseveration to the previous position which could indicate a reference memory/response flexibility problem. The PRO mice where the expression of tau had been switched off and which were tested for behavior, are currently being tested for LTP. Preliminary data indicate that there is no difference between the CTRL mice and the switched-off PRO mice, i.e. the switched-off PRO mice seem to be displaying normal hippocampal synaptic plasticity. The correlative analysis of these mice by biochemical and histological methods is underway. The results are consistent with the view that the toxicity of tau is closely related to its propensity for aggregation, and that the toxicity can be reversed by switching off the expression and hence the aggregation of tau.