The Effect And Mechanism Of Citalopram And Visuospatial Learning Training On AD Like Pathological Changes In Different Alzheimer’s Disease Models

Part 1 The effect and mechanism of citalopram on cognitive impairment induced by social isolated ratsBackground: Alzheimer’s s disease(AD)is the main type of dementia.AD is caused by the combined effects of genetic and environmental risk factors.With the aging of population,social isolation / loneliness has become a common phenomenon in the elderly population and a widespread social problem.Social isolation / loneliness can lead to cognitive decline,which is a high-risk factor for AD.However,the mechanism of social isolation / loneliness causing cognitive decline is not clear,and there is also lack of effective intervention measures.In addition,the selective 5-HT reuptake inhibitor(SSRIs)can increase the 5-HT content in the synaptic gap,promote the synthesis of melatonin in the brain,improve the hippocampal synaptic plasticity and neurogenesis,and give play to the neuroprotective effect of multiple targets.Whether the SSRI class drug citalopram can early intervene the risk factors of AD and play a therapeutic role is not clear.Methods: Middle-aged rats(10 months)were group or isolation reared for 8 weeks.Following the initial 4-week period of rearing,citalopram(10 mg/kg i.p.)was administered for 28 days.Then,pathophysiological changes were assessed by performing behavioral,biochemical,and pathological analyses.Results: We found that SI could cause cognitive dysfunction and decrease synaptic protein(synaptophysin or PSD93)expression in different brain regions associated with cognition,such as the prefrontal cortex,dorsal hippocampus,ventral hippocampus,amygdala,and caudal putamen,but not in the entorhinal cortex or posterior cingulate.Citalopram could significantly improve learning and memory and partially restore synaptophysin or PSD93 expression in the prefrontal cortex,hippocampus,and amygdala in SI rats.Moreover,SI decreased the number of dendritic spines in the prefrontal cortex,dorsal hippocampus,and ventral hippocampus,which could be reversed by citalopram.Furthermore,SI reduced the levels of BDNF,serine-473-phosphorylated Akt(active form),and serine-9-phosphorylated GSK-3β(inactive form)with no significant changes in the levels of total GSK-3β and Akt in the dorsal hippocampus,but not in the posterior cingulate.Conclusions: Our results suggest that decreased synaptic plasticity in cognitionassociated regions might contribute to SI-induced cognitive deficits,and citalopram could ameliorate these deficits by promoting synaptic plasticity mainly in the prefrontal cortex,dorsal hippocampus,and ventral hippocampus.The BDNF/Akt/GSK-3β pathway plays an important role in regulating synaptic plasticity in SI rats.Part 2 The mechanism of spatial training to improve cognitive impairment in PR5 mice through NLRP3/caspase-1/IL-1 beta pathway.Background: Alzheimer’s disease is a neurodegenerative disease characterized by a comprehensive decline in cognitive function,abnormal mental behavior,and loss of daily life ability.The drugs used in clinic are not effective and expensive.At present,AD is thought to have been affected by factors such as gene and environment.In 2015,the Alzheimer’s disease association of the world analyzed the risk factors of dementia,pointing out that low education level will significantly increase the risk of AD.In patients diagnosed with AD,the impairment of cognitive ability of people with high education level will obviously slow down.Cognitive stimulating therapy improves the memory functions with the same efficacy as galantamine or tacrine in AD。More and more clinical and preclinical evidences suggest that cognitive training can improve cognitive function and delay disease progression in AD and MCI patients,but its mechanism is unclear.Methods: 10 month old PR5 transgenic mice and the same born wild type mice were divided into four groups,Wt group,Wt+MWM group,PR5 group,PR5+MWM group.Half of the mice were used novel object recognition test to observe cognitive after spatial training.Another half of the mice were used novel object recognition test to observe cognitive after 3 month later.In addition,PR5 mice were hybridized with NLRP3 knockout mice to obtain NLRP3 knockout PR5 mice.Added PR5/NLRP3+/-+MWM group and PR5/NLRP3-/-+MWM group.The mice were trained 1weeks.After the end of the behavioral study,the hippocampus was isolated.The Western blot were used to detect phosphorylation level of Tau protein,expression of synapse related proteins,expression of NLRP3/caspase-1/IL-1βpathway protein in the hippocampus.Meanwhile,Golgi staining was used to detect the number of dendritic spines.Results: During the 4 week spatial training,the time to platform of PR5 mice in the first week was significantly lower than that of Wt mice.With 4 week spatial training,the time to platform of PR5 mice were decrease.In the 4 week memory test,the percentage target and the target crossing of the PR5 mice in the first week were significantly lower than those of the wt mice.Meanwhile in the four weeks of spatial training,the memory level of PR5 mice increased.After 4 weeks of spatial training,the results of the novel object recognition test showed that the PR5 mice with training were significantly improved in the episodic memory damage of the PR5 mice than the untrained mice.The other half mice still had an improvement in memory after 3 months later.Molecular biological examination showed that the phosphorylation level of p S396 and p T231 sites in PR5 mice increased significantly,and the phosphorylated Tau1 decreased.At the same time,compared with the Wt mice,the number of dendritic spines and the expression of synaptophysin,PSD93 and PSD95 in hippocampus of PR5 mice decreased significantly After 4 weeks of spatial training,Tau protein phosphorylation level,synapse related protein expression and number of dendritic spines in PR5 mice were significantly improved.The expression of NLRP3,caspase-1 and IL-1 IL-1 in hippocampus of PR5 mice increased significantly compared with Wt mice,and the increase of these three proteins was reversed after spatial training.After 3 months later,these indicators still have an improvement trend in the PR5 spatial training group.After NLRP3 knockout,the results showed that the PR5/NLRP3-/-+MWM mice significantly decreased the level of phosphorylation of Tau protein at the p S396 and p T231 sites and increased the phosphorylated Tau1 in the hippocampus compared with the PR5+MWM mice.Conclusion:Long time spatial training significantly improved the cognitive deficits in PR5 mice,and it has a long term effect.Meanwhile,the spatial training may regulate the level of phosphorylation of Tau protein in hippocampus of PR5 mice.Furthermore,these results show an important role for the NLRP3/caspase-1/IL-1β axis in the spatial training ameliorates synaptic plasticity deficits in PR5 mice.