RvD1 Improves Cognitive Function In Alzheimer's Disease

Resolution of inflammation is the optimal outcome after inflammation occurs.Endogenous regulation of inflammation is a hot topic in the biomedical field.In a variety of severe neurological inflammation pathological changes,such as Alzheimer's disease,the resolution of inflammation involves in the disease development and multiple pathological link in the recovery process.Thus,resolution of inflammation provides a new path for the treatment of these diseases.In the early stages of inflammation,endogenous program of resolution of inflammation has already initiated,including specialized pro-resolving mediators(SPMs),which could promote inflammation initiative to resolve and restore the dynamic balance of local internal environment,and finally decide to inflammation intensity and duration.While the abnormal regulating mechanism has been proved closely associated with the occurrence of some diseases.For instance,it is reported that AD patients have worse capacity of SPMs in resolution of inflammation,at the same time,the process of resolution of inflammation also relative delay in aging mice.Above results indicate that SPMs mediated endogenous resolution of inflammation may be involved in a variety of central inflammation pathological process,including AD.Resolvin is a kind of important SPM,It not only promotes the inflammation to subside,but also maintains the relative stability of the internal environment of the body,and regulates the dynamic balance among various elements of the body.As an important member of the extinction hormone family,resolvin D1 is a kind of endogenous anti-inflammatory derived from omega-3 fatty acids lipid molecules,and usually produced by neutrophils and macrophages,which mainly play a role of promoting resolution of inflammation actively.We observed the role of resolvin D1 in inhibiting the inflammatory activation and improving metabolic balance of microglia induced by ?-amyloid,and the influence in the cognitive function of Alzheimer's disease(AD)transgenic mice.Method:1.To observe the effect of Rv D1 on activation of microglia.Microglial cell lines(BV2)were cultured and treated with LPS,or LPS+A?,or LPS+A?+Rv D1.The expression levels of NOD like receptor thermal protein domain related protein 3(NLRP3),apoptosis-related speck like protein(ASC)and Caspase1 were observed via RT-PCR.2.To observe the effect of Rv D1 on mitochondria of microglia.Microglial cell lines(BV2)were cultured and treated with the same as above,the morphological changes of mitochondria in BV2 cells were observed by Mito-tracker Red and confocal microscopy.3.To observe the effect of Rv D1 on hippocampus of AD transgenic mice.The AD transgenic mice received Rv D1 via intraperitoneal injection for 10 days,5mg/(kg·d).Via immunohistochemical staining(IHC),immunofluorescence(IF),real-time fluorescent quantitative PCR(RT-PCR)method,we observe the level of NLRP3 inflammasome pathways,microglial markers(Iba1),and the expression of related factors of regulating mitochondrial metabolism in the hippocampus of AD transgenic mice.4.To observe the effect of Rv D1 on the cognitive function in AD transgenic mice.By the Fear conditioning test(FCT),we investigated the effect of Rv D1 on the cognitive ability of contextual and cue memory of AD transgenic mice.Results: 1.Results showed that Rv D1 inhibited the activation of NLRP3 inflammasome pathways induced by LPS+A?,and protected mitochondrial morphology of BV2.The results showed that the m RNA expression levels of NLRP3,ASC and Caspase1 were significantly increased in the LPS+A? treatment group compared with the LPS pretreatment group.After Rv D1 treatment,the m RNA expression levels of NLRP3,ASC and Caspase1 were significantly reduced.Meanwhile,the confocal imaging results showed that the mitochondria of BV2 formed into clumps and scattered spots after LPS+A? stimulation,suggesting mitochondrial aggregation and fragmentation,and indicated the pathological state of mitochondrial function and cellular energy supply.In the Rv D1 treatment group,the mitochondrial morphology of BV2 cells were well-distributed and restored in a cord-like shape,indicating that the mitochondrial function and energy supply had a recovery trend.2.Rv D1 significantly decreased the expression levels of NLRP3 and Iba1 in the hippocampus of AD transgenic mice.Meanwhile,Rv D1 restored the mitochondrial metabolism,and improved cognitive function of AD mice.According to Immunohistochemical results,AD transgenic mice received intraperitoneal injection of Rv D1 for 10 days showed significantly reduced the number of Iba1+ microglia and NLRP3+ cell,and the m RNA expression of OPA1,PGC1?and PGC1? were markedly reduced,indicating Rv D1 rescued A?-induced mitochondrial dysfunction.In fear condition system experiments,Rv D1 treatment group AD transgenic mice showed significantly more context freezing percent,suggesting that the improved hippocampus-dependent cognitive memory function of Rv D1-treated AD transgenic mice.Conclusion:1.Rv D1 can inhibit the activation of NLRP3 inflammasome pathway and microglia,reduce the levels of inflammation in the hippocampus,eventually improve cognitive function in AD transgenic mice.2.Rv D1 can regulate mitochondrial morphology and function of microglia,maintain mitochondrial homeostasis,and protect mitochondria against external damage.3.Rv D1 can significantly improve the cognitive impairment of AD transgenic mice,reflected in the hippocampus-dependent contextual memory and the hippocampus-independent signal memory.4.The therapeutic effect of RvD1 on AD is likely to be achieved by targeting and regulating the mitochondria of microglia cells,via maintaining the stability of mitochondrial morphology and function to inhibit the activation of NLRP3 inflammasome pathway and make more microglia transform into M2 phenotypes,which contributes to the improved cognitive function in AD transgenic mice.