Antioxidant The SS31Peptides Regulating Hippocampal Tissue Mitochondrial Fission And Fusion Imbalance Improve Senescence-accelerated Mouse-prone Learning And Memory Function

Objectives: Alzheimer’s disease (Alzheimer’s disease, AD) is an age-relatedneurodegenerative disease. Currently, its incidence and prevalence isincreasing, it is becoming a major threat to the health of the elderly, andimpose a heavy burden to families and society. Recent studies have reportedabnormal mitochondrial fission and fusion can lead to Alzheimer’s disease,Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosisand other neurodegenerative diseases occur.Mitochondria is a highly dynamic organelles constantly fission and fusion,mitochondrial fission and fusion in fine dynamic balance, maintaining normalcell morphology and function of normal cells. In mammalian cells,mitochondria fission is mainly affected by the power-related protein-1(dynamin-related protein1, Drp1)、 mitochondrial fussion protein1(fission1,Fis1) regulation, fusion is mainly affected by the mitochondrial fusion protein1(mitofusin1Mfn1), mitochondrial fusion protein (mitofusin2of Mfn2) andoptic atrophy protein1(optic atrophy1, OPA1) regulation. Avidin D(Cyclophilin D, Cypd) is a mitochondrial matrix protein, is closely related toapoptosis and mitochondrial fission. Oxidative stress can lead tomitochondrial fission and fusion barriers, so that mitochondrial fragmented,reduced mitochondrial function, eventually leading to apoptosis. SS31as highcell-permeable peptide antioxidants, have anti-oxidative stress, anti-inflammatory and protects mitochondrial role, an important role from themaintenance of mitochondrial function. Senescence accelerated mice SAMP8(senescence-accelerated mouse-prone8, SAMP8) is the study of aging andanti-aging common animal models also with AD typical pathological features, such as the Aβ deposition, neurofibrillary tangles, synaptic dysfunction,mitochondrial dynamics change, accompanied by the decline of cognitivedysfunction and memory, is also recognized as the ideal model of AD. Thisarticle by studying mitochondrial division and fusion control proteinexpression changes, explore SS31SAMP8mice with learning and memoryfunction to improve the role and possible mechanisms.Methods: The study is divided into two parts: first experiment, SAMP8mice after6months of age, the biological characteristics of the typicalcharacteristics with early Alzheimer’s disease (AD) is basically the same, soselect SAMP8as AD model. SAMR1mice is normal aging, so often used as acontrol. this study,we choose male8to9-month-old SAMR1, SAMP8mice,set up for SAMR1normal control group(Normal), The SAMP8model of thecontrol group(Model), The SAMP8plus saline vehicle control group(Vehicle),and the SAMP8with SS31treatment group(SS31). A total of4groups, eachgroup has10animals. S31drug dissolved with saline before required,andSS31group were given5mg/kg of SS31intraperitoneal injection.The vehiclecontrol group given saline by intraperitoneal injection as same for onceeverday, for two and a half months. After two and a half months, we testmouse with Morris water maze for navigation place test and spatial probe test,according to the results, we confirm that whether can improve learning andmemory function with SS31. The second experiment, we measured the Drp1,OPA1, Cypd protein expression of hippocampal tissue with mice usingwestern-blot method. And, we used RT-PCR test for the mRNA of Drp1,OPA1and Cypd expression. Investigate the SS31whether by adjusting themitochondrial power related protein expression, may play an anti-aging andtreatment of age-related diseases such as AD.Results:1Morris water maze test:1.1The test of place navigation: In2d,3d,4d,5d,6d, Test the mice’s learning,the results of learning function revealed that: 1.1.1Escape lantency: Compared with Normal group, the escape lantency ofModel group had longer significantly (P<0.05); the escape latency has noobvious change in group Vehicle compared with Model (P>0.05); escapelatency in mice SS31group was obviously reduced(P<0.01).1.1.2Swimming distance for looking platform under water: Compared withNormal group, the swimming distance for looking platform under water ofModel group had longer significantly (P<0.05); the swimming distance forlooking platform under water has no obvious change in group Vehiclecompared with Model (P>0.05); swimming distance for looking platformunder water in mice SS31group was obviously reduced(P<0.01).1.2Space exploration experiment: At the7day, test mice swimming time inthe platform quadrant. The recults was: Compared with Normal group, theswimming time in the platform quadrant of Model group had shotersignificantly (P<0.05); the swimming time in the platform quadrant has noobvious change in group Vehicle compared with Model (P>0.05); swimmingtime in the platform quadrant in mice SS31group was obviously lengthened(P<0.01).2After application of antioxidants SS31, the Drp1, OPA1and Cypdexpression in hippocampus of SAMR1and SAMP8mouse:2.1Compared with Normal group, the total protein expression and mRNAlevel of Drp1in Model group were elevated, but those were nosignificant(P>0.05); compared with Model group, the protein expression andmRNA level of Drp1in Vehicle were no change (P>0.05), but in SS31groupwere declined, but those were no significant(P>0.05).2.2Compared with Normal group, the total protein expression and mRNAlevel of OPA1in Model group were declined, those were significant(P<0.05);compared with Model group, the total protein expression and mRNA level ofOPA1in the Vehicle group were no change(P>0.05), but in the SS31groupwere elevated, those were significant(P<0.05).2.3Compared with Normal group, the total protein expression and mRNAlevel of Cypd were elevated, those were significant(P<0.05); compared with Model group, the total protein expression and mRNA of Cypd in the Vehiclegroup were no change(P>0.05), but in the SS31group were declined, it wassignificant(P<0.05).Conclusion:1The study by Morris water maze test suggest that the AD model SAMP8mice with learning and memory dysfunction, the SS31drug can improveSAMP8mice learning and memory function.2This study shows that in the the SAMP8mouse hippocampusmitochondrial fission and fusion protein expression abnormalities, throughSS31intervention can change the expression of mitochondrial powerrelated protein Drp1, OPA1and mitochondrial matrix protein Cypd toimprove mitochondrial function, thereby preventing neural elementsapoptosis, improve the symptoms of AD, for AD disease treatmentprovides a theoretical basis.