Cognitive Impairment Induced By Insulin Resistance

Background Alzheimer’s disease(AD)is a progressive neurodegenerative change,which is characterized by the progressive decline of memory and cognitive function,behavior and personality changes.More and more evidences show that AD is also a metabolic disease mediated by cerebral insulin reactivity,glucose utilization and energy metabolism disorders,leading to increased oxidative stress,inflammation and worsening insulin resistance.It is one of the complications of Type 2 diabetes mellitus(T2DM)in type two diabetes.Insulin resistance(IR)is defined clinically as that a known amount of exogenous or endogenous insulin can not increase individual glucose uptake and utilization as in normal population,which is considered to be the most important feature of T2 DM.Polo like kinase family is a highly conserved serine /threonine kinase family that plays an important role in cell cycle regulation.It contains five known members(PLK1-5)and is considered to be proto oncogenes.Recent studies have shown that polo like kinase family members are involved in the pathological process of neurodegeneration such as AD.The previous research of the research group found that the phenomenon of "spontaneous insulin resistance" was found in normally raised C57 BL / 6 mice.Combined with 90% of AD cases,it may be the key inducement of AD pathogenesis,which can better simulate the pathological process of T2 DM patients developing into ad.Objective This study will take "spontaneous insulin resistance" mice as a model to explore whether PLKs play a role in the pathology of T2 DM and AD,and try to clarify the molecular mechanism,hoping to provide new ideas for the association between the two diseases and provide targets for the research of related drugs.Method Firstly,11.5-month-old wild type(WT)mice were fasted for 16 hours before the experiment,their fasting blood glucose was measured,and the serum was prepared by tail vein blood collection.The fasting insulin level was measured by ELISA experiment,and the spontaneous insulin resistance mice were screened by homeostasis assessment model(HOMA).Secondly,we evaluated whether the emotional,memory and cognitive functions of mice had changed through animal behavior.Thirdly,we explored whether PLKs play a role between T2 DM and AD by RT-PCR.Finally,we detected PLK2 and PLK5 in WT mice and 5×FAD by Western blot.The expression in the cortex and hippocampus of fad mice,and WT mice and 5 were detected by microdialysis Changes of glucose and mannose in cerebrospinal fluid of WT mice and5×FAD mice.Result In animal behavioral experiments,we found that insulin resistant mice showed significant differences in T maze and novel object recognize;There was a trend of despair behavior in tail suspension and force swimming test,but there was no statistical difference;There was no significant difference in other items.In addition,we found PLK5 in spontaneously insulin resistant mice and 5×FAD The m RNA expression level of cerebral cortex in 5×FAD mice decreased,while PLK2 decreased in some individuals.At the same time,we also found that PLK2 and PLK5 were in IR group and5×FAD.The change trend in the hippocampus of 5×FAD group was the same,and there were significant differences.In addition,we also found abnormal glucose and mannose metabolism in the brain of spontaneously insulin resistant mice;And there were differences in mannose content in cerebrospinal fluid of 5×FAD mice,but there was no significant change in glucose content.Conclusion Our study found that spontaneous insulin resistance mice had abnormal brain glucose and mannose metabolism,while 5×FAD The fad group only showed abnormal mannose metabolism.In addition,the changes of PLK2 and PLK5 expression in hippocampus suggest that they play a role between T2 DM and AD.