| Objective:The objective of this study was to investigate the intervention and interaction effects of aerobic exercise（AE）and oyster peptide（OP）on the formation of Alzheimer’s disease（AD）rat induced by D-galactose（D-gal）combined with sodium nitrite.Based on the fibronectin type III domain-containing protein 5（FNDC5）/irisin-cAMP reaction element binding protein（CREB）-brain-derived neurotrophic factor（BDNF）signaling pathway,this study explored the biological mechanism of AE combined with OP supplementation to interfere with hippocampal synaptic plasticity in the process of AD formation,and explored the Cross-talk between skeletal muscle and brain,so as to clarify the role of the muscle-brain axis in the prevention of AD.Methods:12-week-old healthy SD rats were randomly divided into NC control group（NC,n=10）,AD control group（ADC,n=10）,AD with aerobic exercise intervention group（ADE,n=10）,AD with OP intervention group（ADOP,n=10）and AD+aerobic exercise+OP intervention group（ADEOP,n=10）.The NC group did not perform exercise training,while the ADC,ADE,ADOP and ADEOP groups were given intraperitoneal injection of D-gal and oral sodium nitrite to induce AD formation.ADOP and ADEOP groups were given OP supplement at a dose of 1.0g/Kg body weight every morning.ADE and ADEOP groups were performed 60min swimming training without weight-bearing every afternoon,5 times a week.ADC and ADOP groups did not perform exercise training for 8 weeks.Morris water maze test was performed 1 week before sampling to determine the learning and memory function of rats in each group.Irisin of plasma,muscle and hippocampus,hippocampalβ-amyloid 42（Amyloid β42,Aβ42）,BDNF and CREB content were determined by ELISA;RT-PCR was used to detect the mRNA expression of FNDC5,CREB,BDNF,Postsynaptic dense protein 95（PSD95）and synaptophysin（SYP）in hippocampus and FNDC5 in skeletal muscle;Western-blot method was used to detect the protein expression of PSD95 and SYP in the hippocampus of rats in each group.Results:（1）Compared with the NC group,the escape latency from day 2 to 5 in the ADC group was significantly prolonged（P<0.01）,the number of crossing platforms was significantly decreased（P=0.000）,and the content of Aβ42 in the hippocampus was significantly increased（P=0.041）.Compared with ADC group,except for ADOP group on day 3,ADOP group,ADE group and ADEOP group had significantly shorten escape latencies on days 3-5（P=0.097,P=0.011,P=0.000;P=0.02,P=0.000,P=0.000;P=0.007,P=0.000,P=0.000）,the number of crossing platforms was significantly increased（P=0.004,P=0.043,P=0.000）,and the Aβ42 content was significantly decreased（P=0.002,P=0.001,P=0.000）.Compared with the ADE group,the escape latency on days 2-5 in the ADEOP group was significantly reduced（P<0.05）,the number of crossing platforms was significantly increased（P=0.004）,and the Aβ42 content had a further decreasing trend,but no significant difference（P=0.532）.（2）Compared with the NC group,the mRNA and protein expressions of PSD95 and SYP in the hippocampus in the ADC group were significantly decreased（P=0.019,P=0.034;P=0.043,P=0.045）.Compared with ADC group,PSD95 mRNA and protein and SYP mRNA expression were increased in ADOP and ADE groups,but there was no significant difference（P=0.289,P=0.055;P=0.061,P=0.054;P=0.227,P=0.188）,the expression of SYP protein was significantly increased（P=0.044,P=0.038）.However,the mRNA and protein expressions of PSD95 and SPY were significantly increased in the ADEOP group（P=0.041,P=0.006;P=0.003,P=0.006）.Compared with the ADE group,the mRNA and protein expressions of PSD95 and SYP in the hippocampus of the ADEOP group had a tendency to further increase,but there was no significant difference（P=0.892,P=0.448;P=0.074,P=0.448）.（3）Compared with the NC group,the FNDC5 mRNA expression in soleus muscle and the content of irisin in soleus muscle,plasma and hippocampus in the ADC group were significantly decreased（P=0.043,P=0.021,P=0.024,P=0.003）.The mRNA expression and protein content of CREB and BDNF in the hippocampus were significantly decreased（P=0.035,P=0.041;P=0.049,P=0.025）.Compared with the ADC group,the soleus muscle FNDC5 mRNA expression and the soleus muscle irisin content and the plasma irisin content were significantly increased in the ADE,ADOP and ADEOP groups（P=0.001,P=0.023,P=0.000;P=0.006,P=0.01,P=0.003;P=0.01,P=0.027,P=0.01）.ADOP,ADE and ADEOP groups in hippocampal FNDC5 mRNA expression and the irisin content in the ADOP and ADE groups had no significant increase（P=0.609,P=0.327,P=0.814;P=0.133,P=0.199）,but irisin content in the ADEOP group was significantly increased（P=0.01）.The hippocampal CREB mRNA was significantly increased in the ADE,ADOP and ADEOP groups（P=0.000,P=0.036,P=0.000）,and the CREB content was significantly increased in the ADEOP group（P=0.006）.At the same time,the hippocampal BDNF mRNA was significantly up-regulated in the ADEOP group（P=0.011）,and BDNF content was significantly increased in the ADE group（P=0.042）.Compared with the ADE group,the expression of FNDC5 mRNA in the soleus muscle of the ADEOP group was significantly increased（P=0.043）,while the contents of irisin in the soleus muscle,plasma and hippocampus,and the mRNA expression and content of CREB and BDNF were not significantly increased（P>0.05）.Conclusions:（1）D-gal combined with sodium nitrite can down-regulate the FNDC5/IrisinCREB-BDNF pathway,reduce hippocampal synaptic plasticity,and induce the formation of AD.（2）AE or supplementation of OP when D-gal combined with sodium nitrite induces AD formation can inhibit the generation of Aβ,improve the FNDC5/irisin-CREB-BDNF signaling pathway,reduce the damage of hippocampal synaptic plasticity,effectively delay the decline of learning and memory ability and play a very important role in preventing the formation of AD.The effect of AE combined with OP supplementation is better than simple AE to a certain extent.As a new target for enhancing synaptic plasticity,irisin plays an important regulatory role in the " muscle-brain cross-talk". |
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