| Objective: Down Syndrome(DS)cause neurodegeneration.Studies have demonstrated that SP and NFTs are present in the brain of DS patients,which is consistent with the characteristic pathological changes of AD patients.Our previous study show that the expression of plasma VA and RARα is significantly decreased in DS patients,while the level of Aβ is significantly increased,and the expression of ADAM10 is positively correlated with RARα expression level.In addition,SP is significantly increased in the brain of AD mice with MVAD.It has been demonstrated that VA regulates the PI3K/Akt signaling pathway through RARα and affects the expression of related molecules,which may be related to the formation of Aβ and deposition into the brain.Our stdudy is aimed to explore relationship between VA and mechanism of DS neurodegenerative changes mediated by Aβ.Methods: Ts65 Dn female mice and special male mice were caged together to breed their offspring.Mice aged 8-10 weeks were selected and fed with VAN or VAD,respectively,to establish the disease models.They were randomly divided into four groups: Ctl +VAN,Ctl +VAD,Ts65Dn+VAN and Ts65Dn+VAD groups.1.Behavioral tests: After four weeks of VAN or VAD feeding,Morris water maze was performed to test the learning and memory function of mice.2.Analysis of serum VA: Mouse serum VA concentration was determined by HPLC.3.In vitro electrophysiological assays: LTP induced changes in synapses of the hippocampus CA1 region were detected and recorded by patch clamp technique.4.Immunohistochemical study: The brain was fixed in 4% paraformaldehyde,and the light microscope was used to observe and count senile plaques after immunohistochemical staining.5.PCR and Western blotting: cortical and hippocampal related molecules and proteins were analyzed.Results: 1.4 weeks after fed with VAN or VAD,serum retinol level in the VAD group were significantly lower than those in the VAN group(P<0.001).2.Learning and memory function of the VAD group was significantly impaired compared with the VAN group: the escape latency was significantly prolonged during the water maze training stage(Ts65Dn mice P < 0.05),and the last day’s test also showed that the residence time in the target quadrant and the number of crossing the platform were shorten(P < 0.05).The memory function inTs65 Dn was significantly impaired compared with those in Ctl: the escape latency was significantly prolonged(P < 0.05 in VAD group),and the number of crossing the platform was reduced in the test stage(P < 0.05).There is an correlation between VA nutrition level and the down syndrome-ralated state on the escape latency(P=0.0102),suggesting that the lack of VA and the disease state of down syndrome both have affect on the spatial learning and memory ability,resulting in impaired memory function.3.In electrophysiological experiment,the hippocampal CA1 LTP was significant impared in the VAD group(P < 0.05),while there was no significant difference between Ctl and Ts65 Dn.4.Immunohistochemical data suggested that there was no senile plaque deposition in the brain of Ts65 Dn rats.5.Compared with VAN group,the expressions of RARα(P < 0.01),claudin-5(P < 0.01),Occludin(P < 0.001),ZO-2(P < 0.05)and GSK3-β(P < 0.05)in VAD group were significantly lower.The expression levels of RARα(P < 0.001,VAN group),PI3K(P < 0.001),Akt(P < 0.001),ADAM10(P < 0.01),Occludin(P < 0.001),ZO-2(P < 0.05),BAD(P < 0.01)and GSK3-β(P < 0.001)in Ctl mice were significantly lower than those in Ts65 Dn mice.Two-way ANOVA showed that the expression of RARα(P=0.009),Occludin(P < 0.001),and GSK3-β(P=0.026)is correlated with VA nutrition level and disease status of down syndrome.6.Western blotting showed that the expression of ZO-2 in the VAD group were lower than that in the VAN group(P < 0.05),and the expression of ZO-2 in Ts65 Dn mice was higher than that in Ctl mice(P < 0.05).Claudin-5 expression in Ctl mice group were significantly higher than that in VAD group(P < 0.05).Conclusion: VA deficiency may reduce the learning and memory ability and prominent plasticity of hippocampus,aggravating the cognitive dysfunction of DS.VA can activate the PI3K/Akt signaling pathway through RARα to affect the expression of BBB tight junction protein,and its deficiency can damage BBB.Therefore,VA plays a pivotal role in the pathological mechanism underlining DS neurodegeneration. |
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