The Neuroprotective Effects Of A Novel Antidiabetic Drug On Cognitive Impairments And Pathology In Streptozotocin-induced Alzheimer Rat Model

Objective:To explore whether DA-JC4,a new GLP-1/GIP double agonists,could effectively amelioratethe impairment of working memory and spatial learning and memory ability in streptozotocin-induced Alzheimer rat model,reduce tau phosphorylation,decrease inflammation and apoptosis.In addition,we further investigated the relation between neuroprotective mechanism of DA-JC4 and brain insulin signaling pathway.Methods:1.Rats were randomly divided into four groups: 1)Control group: artificial cerebral spinal fluid(aCSF)intra-cerebral ventricular(ICV)injection plus saline intraperitoneal(IP)injection;2)DA-JC4: aCSF ICV injection plus dual agonists IP injection;3)STZ group: STZ ICV injection plus saline IP injection;4)STZ + DA-JC4 group: STZ ICV injection plus dual agonist IP injection.Each rat was treatment with DA-JC4(10 nmol/kg ip.)or saline once-daily for 2weeks after STZ intracerebroventricular(ICV)administration.And behavior effects of DA-JC4 were tested by Y-maze and Morris water maze.2.Immunohistochemistry was used to observe the levels of tau phosphorylation and the numbers of GFAP-positive astrocytes and IBA1-positive microglia in the brain3.Protein expression levelsof apoptosis-related molecules,such as BAX and Bcl-2,and insulin signaling pathway-related molecules,such as IRS1 and Akt,were quantified by Western blot.Results:1.Y-maze and Morris water maze showed that rats receiving STZ ICV injection alone have significant lower memory behavior scores in spontaneous alternation and space exploration than control group.Compared with STZ group,DA-JC4 could statistically improve memory deficit.2.Compared with control group,STZ increased the levels of tau phosphorylation in the cortex and hippocampus.This change was reversed by treatment with DA-JC4.3.Compared with control group,STZ increased the number of GFAP-positive astrocytes and IBA1-positive microglia in the cortex and hippocampus.The number of these positiveneuroglia cells in treatment group were significantly lower than STZ group.4.Compared with control group,STZ could increasedthe ratio of pro-apoptotic BAX to anti-apoptotic Bcl-2 protein expression levels.This ratioin the cortex and hippocampus was partly reversed after DA-JC4 treatment.5.Compared with control group,STZ treatment elevated IRS1(pSer1101)but suppressed Akt(pSer473).However,DA-JC4 effectively attenuated the STZ-induced these change.Conclusion:1.DA-JC4 treatment could effectively alleviate the impairment of multiple learning and memory ability induced by STZ and partly reversed the decline of cognitive.2.DA-JC4 could reduce tau phosphorylation in the brain of the Alzheimer icv.STZ rat model to avoid its highly phosphorylation and delay the formation of nerve tangles.3.DA-JC4 could significantly reduce the number of GFAP-positive astrocytes and IBA1-positive microglia in the brain and further relieve the chronic inflammation induced by STZ.4.DA-JC4 would perform anti-apoptotic effects in the cortex and hippocampus by which regulate with the protein expression of pro-apoptotic BAX and anti-apoptotic Bcl-2 to inhibitSTZ-induced neuronal apoptosis.5.DA-JC4 would down-regulate p-IRS1 and up-regulate p-Akt,which supports the neuroprotective effect of DA-JC4 against STZ-induced brain insulin resistance.