The neuroprotective effects of fluoxetine on the neurons and synapses in the hippocampus of the middle-aged APP/PS1 mice

【摘要】：Objective In order to understand the reasons for the neuroprotective effect of fluoxetine(FLX) on Alzheimer's disease(AD), the current study investigated the effects of FLX on the neurons and synapses of the hippocampus in the middle-aged APP/PS1 mice. Methods Forty 16-17 month-old male APP/PS1 mice were respectively randomly assigned to control group(APP/PS1) or treated group(APP/PS1+FLX). Meanwhile, the wild-type(WT) mice with the same age were considered as normal control group. All mice in three groups were randomly assigned to receive systemic administration of either fluoxetine(10 mg/kg i.p. dissolved in 0.9 % Na Cl) or vehicle(equivalent 0.9 % Na Cl i.p.) once per day in the morning between 9 AM and 10 AM for 5 consecutive weeks. In the 5 th week, the Morris water maze was performed to assess the spatial learning and memory abilities. Immunohistochemical staining was used to examine the effect of FLX on the deposition of beta amyloid in middle-aged APP/PS1 mice. Western blotting technique was conducted to investigate the effect of FLX on the protein expressions of Tau and Phospho-Tau(Ser396) in the middle-aged APP/PS1 mice. Immunohistochemical staining and the stereological analyses were performed to investigate the effect of FLX on the number of neurons and dendritic spine synapses in the hippocampus of middleaged APP/PS1 mice. Results In the hidden platform trials, the middle-aged APP/PS1 mice revealed significantly higher increasing escape latencies compared with the WT mice(p 0.01), while the escape latency of the APP/PS1 mice in the FLX-treated(APP/PS1+FLX) group was markedly lower than the latency of the mice in the APP/PS1 group(p 0.05). In the subsequent probe task, the frequency at which the mice crossed the platform location was not statistically different among the three groups. There was hardly any aggregation of beta amyloid in the hippocampus in the WT mice, but in the APP/PS1 and APP/PS1+FLX mice, beta amyloid was found to have aggregated in the hippocampus. The level of Phospho-Tau(Ser396) was significantly lower in the FLXtreated APP/PS1 mice than in the APP/PS1 mice(p 0.05), while there was no significant difference in the level of Tau among the three groups. The number of neurons in DG of the hippocampus in middle-aged APP/PS1 mice was significantly lower than that in WT mice, while the number of neurons in DG of FLX treated middle-aged APP/PS1 mice was significantly higher than that in untreated APP/PS1 mice. However, there were no significant differences in the numbers of neurons in CA1 and CA2/3 of hippocampus among three groups of mice. The numbers of spinophilin-immunoreactivity dendritic spines in DG, CA1 and CA2/3 of hippocampus in middle-aged APP/PS1 mice are being collected. Conclusions FLX can rescue the learning ability impairment of middle-aged APP/PS1 mice. FLX can reduce the deposition of beta amyloid and inhibit the hyperphosphorylation level of Tau in the middle-aged APP/PS1 mice. FLX can prevent the neuron loss in the DG of hippocampus in the APP/PS1 mice.