Effects Of APP17Peptide On The Improvement Of Diabetic Encephalopathy And The Correlation With Insulin Signal Pathway

Diabetic encephalopathy attributes to the injury and pathological diabetesinduced central nervous system and other end-organs, cognitive behavioral defects asthe main features.Diabetic encephalopathy acquired cognitive behavioral disorder asthe main features of the learning process of memory, analysis, problem-solving ability,thinking, intelligence and reaction speed to have a larger impact on type1diabetesand type2diabetes can occur. The diabetic encephalopathy was an accelerated brainaging process. Type1diabetes patients mainly have pathologicallesionin the abilitiesof encephalopathy associative memory, learning skills and attention tocognitive,dysfunction of type2diabetes patients occurs in learning and memory, suchas the main memory extraction process defects. Many factors induce diabeticencephalopathy, in addition, diabetes-related peripheral atherosclerosis and vasculardisease can increase the risk of suffering from diabetic encephalopathy, long-termsmoking increases the risk of cognitive dysfunction. In addition, there is negativecorrelation between the incidence of dementia and education, also was related togenetic factors and gender.Diabetic encephalopathy is caused by many complex factors, multiple aspects ofinteractions, it is the complexity of the pathogenesis, so far without a clearexplanation. APP hydrolysis occurs mainly at the cell surface and the Golgi apparatus,the alpha secretion after enzyme hydrolysis, α amyloid precursor protein, soluble Nfragment, called secretory beta-amyloid precursor protein alpha (sAPP α). Secretionto the extracellular, exert neurotrophic and nerve repair are accelerated with thegrowth of cell and nerve cell axons occurrence function.In recent years, with theincidence rate increased year by year, gets more and more attention. Clinical treatmentbasically is in the control of blood glucose, in order to reduce the occurrence ofdisease of the nervous system, anticholinergic drugs are used in the treatment,vasodilators such as neuroprotective agents, but the effect treatment is not optimistic,and the drug for its pathogenesis is still under development.Amyloid precursor protein (APP) exists in various tissues and cells of vertebrates and mammals widely, almost all cells can synthesize APP, especiallyit has high levelof expression in neurons.The peptide, that was the position319-335in Amino Acidsequence of APP, named APP17peptide, it composed of17amino acids, and it hasmolecular weight of2.1kDa,.APP17peptide can promote the expression of a varietyof neurotrophic factor, including up-regulation of neuronal cell survival signalingpathway related protein level, the expression of apoptosis factor. It can also affect theprotein metabolism of the nerve cells to play a protective effect of nerve cells,prevention ultrastructure and neural degenerative diseases of the nervous system,eventually learning, memory capacity improved.Established by the method of STZ-induced type2diabetes model, and then wetake advantage of the Morris water maze screened encephalopathy rat model ofcognitive dysfunction in diabetes. APP17peptide after treatment, the observedchanges in blood glucose, body weight, and memory capacity of the rat model, theapplication of PET/CT technology to detect the rats brain glucose metabolism, andthe RT-PCT, Western blot, immunohistochemicalwere applied to study diabeticencephalopathy rat hippocampus major factor IGF1R, IR and Glut4expression.Experimental results show that the model rats had significantly more food, polydipsia,polyuria and weight loss,"more than three a little" performance, and the emergence ofmemory loss and cognitive decline typical diabetic encephalopathy characterized. Theresults also indicate that the APP17peptide treatment given to different doses of therat model and found that it does not improve blood sugar levels and body mass indexof diabetic encephalopathy rats, but has significantly improved the memory functionof rat model. Compared with the normal control, SUV in diabetic encephalopathy wassignificantly lower, and that of APP17peptide treatment groups was significantlyhigher than that of diabetic encephalopathy group, all above results suggestedthatAPP17peptide can improve glucose metabolism of rats with diabeticencephalopathy. By examining several main proteins in brain hippocampus of modelrat, APP17peptide can significantly promote the expression of Glut4, suggesting thatcognitive dysfunction APP17peptide to improve diabetic encephalopathy rats may berelated to its action to IGF1R.The lenti-viral packaging transfection technology was used in obtaining IGF1RKnock-out cells, namely ΔIGF1R-PC12cell lines.was inhibited by G418selection.This cell model is a very useful tool to reveal the details of mechanism in improvingthe cognitive dysfunction of diabetic encephalopathy rats by APP17peptide. WST-1 assay was used in detecting the killing effect of APP17peptide on PC12cells, theresultsindicated that it has no apparent side effects on PC12cells in0.5μg/mL dose,the dose was used in following studies. The resultsshowed that insulin stimulatedphosphorylation of PC12cells, IR given APP17peptide had stronger affinity forinsulin performance, approximately only need insulin concentrations of1/10,indicating APP17peptide can enhance the PC12cells IR islet affinity. When IGF1Rdefect-expression occurs, the effect of APP17peptide causedserious declineinIGF1-induced phosphorylation levels. These prove thatAkt and PI3K is twoimportant nodes in improving glucose metabolism of APP17peptide on PC12, namelythe PI3K-Akt Pathway showed important biological role in APP17peptide’streatment on Diabetic encephalopathy.The research results show that the effect of APP17peptide improved insulinsensitivity PC12cells IR phosphorylation, the trigger of the mechanism may berelated to the inhibition of IGF1R pathway by APP17, in the downstream of APP17peptide’ treatment, PI3K-Akt Pathway play important role in improving glucosemetabolism.In this paper, STZ-induced screening and Morris water maze wassuccessfullyused to established model of diabetic encephalopathy, and confirmed that APP17peptide has an effect to improve the rat model of cognitive function, further found thatin the IGF1R APP17peptide to improve the role of the insulin-signaling pathway isclosely related toIR，IGF1R and PI3K-Akt pathway. The results study has providednew ideas and targetfor the treatment of diabetic encephalopathy.