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It can therefore be seen as the most sophis ticated method for the quantificati

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It can therefore be seen as the most sophis ticated method for the quantificati

Сообщение  wangqian в Чт Май 15, 2014 12:08 pm

Thus, in this experimental para digm younger FDDKI mice show no memory deficits. Having established that inhibition of secretase does not ameliorate memory deficits of FDDKI mice, we took advantage on this experimental set ting in which FDDKI mice perform equally well as WT mice, to determine whether GSI could have a detrimen tal ABT-888 価格 effect on memory. To this end, the day after the first NOR test shown in Figure 2, FDDKI mice were injected once, one hour before the training test, with either 1ul of PBS or 1ul of a 3uM solution of compound E in PBS. GSI treated mice explored the two identical objects simi larly to the PBS treated animals. When these mice were subjected to the trial test with the new object, GSI treated FDDKI mice showed a statistically significant memory deficit as compared to vehicle treated FDDKI mice.<br><br> Overall, these data show that inhib ition of secretase produces a worsening rather than amelioration of the memory deficit of FDDKI mice. These data are consistent Afatinib 溶解度 with the Phase III clinical trial with the GSI Semagacestat in AD patients. Inhibiting secretase causes accumulation of APP COOH terminal fragments The dose of GSI injected was chosen based on the following rationale. The IC50 for com pound E is 240 370 pM. We have estimated that after injection compound E is diluted in the CSF of the lateral ventricles 200 folds. Considering that clearance and distribution of the drugs in various area of the CNS further dilutes the GSI, it can be safely pre sumed that the concentration of the GSI in the hippocam pus of mice during the course of the experiment was not excessively high.<br><br> To determine whether this GSI dosage was sufficient to yield some level of inhibition of secretase ac tivity, we AG-1478 分子量 measured B CTF and CTF, which increase when secretase is inhibited. Because novel object recognition is a hippocampal dependent memory task and synaptic activ ity is associated with learning and memory, we measured the levels of these APP fragments in purified hippocampal synaptosomes. As shown in Figure 4a, b, the levels of both B CTF and CTF were significantly increased in mice trea ted for 5h with compound E as compared to untreated ani mals. In contrast, the levels of mature APP and mature Bri2 were unaffected by the GSI. The increase in APP CTFs in hippo campal synaptic preparations resulted in significantly higher B CTF mAPP and CTF mAPP ratios in GSI treated mice as compared to control mice.<br><br> These data indi cate that injection of 1ul of a 3uM solution of compound E was sufficient to measurably inhibit secretase activity and processing of B CTF and CTF by secretase. Discussion We have previously shown that the synaptic plasticity and memory deficits in FDD are mediated through pro duction of sAPPB and or B CTF during LTP and mem ory acquisition. The failure of GSI to rescue the deficits of 9 10 month old FDDKI mice suggests that AB, P3 and AID AICD, the metabolites derived from cleavage of APP, are not involved in these pathogenic processes. Younger FDDKI mice showed no memory deficits when subjected to NOR tests with a shorter retention time.


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