Cognitive Function, Metabolism Of Amyloid Precursor Protein And Effect Of Pioglitazone Intervention In The Brain Of Insulin Resistance Rats

BackgroundWith the aging of population, the incidence of Alzheimer's disease is increasing in world. Alzheimer's disease has brought the serious burden for the patient and society. At present, though it is identified in clinic, the pathogenesis of Alzheimer's disease is unclear and there are also no effective treatment methods. Many domestic and foreign clinical researches demonstrated that the insulin resistance is one of hazard factors on cognition damage. In recent years, more and more researchs have been reported that insulin resistance is associated with Alzheimer's disease. But the specific molecular mechanism of it is still unclear. Therefore, the exploration on the molecular mechanism between insulin resistance and Alzheimer's disease has the very vital significance.The vitro experiment already discovered that insulin can affect the metabolism of Amyloid Precursor Protein (APP), thus regulate the production and transportation ofβ-amyoid protein. In addition, there has been reported that insulin resistance contributes to produce insolubleβ-Amyloid and the phosphor-tau protein. But there hasn't enoughly reported that insulin resistance affects the expression of APP or its related enzyme.At present, the methods to improve the insulin resistance include doing more exercises, diet intervention and the insulin-sensitizing agents. Pioglitazone is a new kind of insulin-sensitizing, belongs to thiazolidinediones, and may only through activating PPARy display function. There has been reported that PPARy agonist can improve cognition function in minor AD patients. The researches above suggested that from the insulin resistance's angle to treat AD will be possible to obtain certain curative effect.ObjectiveMy study was to explore the cognitive fuction and vigor of choline acetyltransferase in insunlin resistace rats, and to explore the expression of APP or its related enzymes, and the effect of pioglitazone intervention in the brains of insulin resistance rats.Methods6～8-week-old Wistar male rats were fed with frucotose to develop insulin resistance model for 4 weeks. Insulin resistance rat model were randomly divided into IR group (n=13) and pioglitazone (PIO) group (n=13). Rats in PIO group were given with pioglitazone 10mg/(kg-1·d-1) by gavage for 12 weeks. The congnition ability of rats was assayed with Morris water maze test. The expressions of Aβ42 were detected with immunohistochemistry. Western blot was employed to examine the levels of APP, BACE-1, PS-1 and IDE proteins. The activity of choline acetyltransferase was detected by chemical coloration. Sections were stained with methyl aniline blue and cells in the hippocampus and cortex were observed with microscope.Results1. The comparison of quality, blood glucose, fasting insulin and insulin resistance index in three groups of ratsComparedwith NC group, the level of quality in IR and PIO groups decreased but have no significantly difference (P>0.05). The level of fasting insulin and insulin resistance index in IR and PIO group increased significantly than NC group (P<0.01, P<0.05). The level of fasting insulin and insulin resistance index in PIO group decreased significantly than IR group (P<0.01).2. The result of Morris water maze testThe result showed that the escape latency was longer in IR and PIO group than in NC group (P<0.01, P<0.05).3. The activity of ChATCompared with normal group, the activity of ChAT decreased significantly in IR group (P<0.01). the activity of ChAT in PIO group was higher than IR group rats (P <0.05), but it was lower than normal rats (P<0.01).4. The expression of Aβ42 in hippocampus was detected by immunohistochemistryImmunohistochemistry results indicated that the optical density of Aβ42 in the hippocampus of the IR and PIO groups was significantly higher than that of the NC group, and was lower in the PIO group than that of the IR group(P<0.01).5. The results of western blotWestern blot showed that APP, BACE-1 and PS-1 levels were elevated in the IR and PIO groups compared with that in the normal controls, and the concentrations in the PIO group was lower than that of the IR group (P<0.05). The expression of IDE protein in IR and PIO groups was lower than that of the NC group, and compared with IR group, The expression of IDE in PIO group was significantly increased (P<0.01).6. The pathological measure of hippocamps in groups (Nissl's staining)In normal group, Nissl's staining showed that the shape of nerve cell, nuclear membrane and nucleolus were seen clearly. The shape of nerve cell was destroyed in insulin resistance rats, the distance of cells increasing, Nissl body disappeared or decreased. Compared with IR group, PIO group was better off.Conlusion1. Cognition function disorder in insulin resistance rats is related to the activity of ChAT decreased.2. The levels of APP, BACE-1, and PS-1 protein in IR rats were increased, while the expression of IDE was decreased. It is possible that insulin resistance promotes Aβ42 by up-regulating the activities of BACE-1, PS-1 and ihbiting the activity of the IDE.3. Pioglitazone therapy can improve cognition function in IR rats, which is related to its effect of increasing the activities of ChAT and its effect of APP or its related enzymes.