Microenvironmental Changes And Mechanisms Of Retinal Inflammation Associated With Alzheimer's Disease

Background:Alzheimer's disease is a common degenerative disease of the central nervous system.The two typical pathological changes as:between nerve cells in the gathered a large number of senile plaques(SP)and neural intracellular neurofibrillary tangles(NFT).SP is mainly composed of amyloid-?(A ?),while the core component of NFT is composed of tau which is abnormally hyperphosphorylated Studies have shown that A ? has the effect of neurotoxin,which can cause the dysfunction and chronic inflammation of A ? variety of cells in the nervous system.At the same time,studies have shown that A ? still exists in the retina.In addition,some age-related ocular fundus diseases,such as age-related macular degeneration,have been proved to be also inflammation-related diseases,but the specific mechanism of causing inflammation and the role of A ? in it have not been clearly expounded.Objective:1.To detect the expression levels of M1 and M2 types of fundus macrophages in AD model mice and their distribution characteristics in retina and choroid,and to explore the changes of retinal inflammatory microenvironment;2.To detect the expression and distribution characteristics of fundus A ? in AD model mice and its relationship with the age of model mice,and to explore the relationship between the presence of A ? and the change of retinal inflammatory microenvironment;3.Detect the effect of A ? on RPE cells,and further explore that the change in the expression of mmp-9 in RPE cells will affect the recruitment of M1-type and M2-type macrophages.Methods:Methods:1.This topic selection of genetically modified APP/PS1 mice as the AD model rats,set up in 9 and 12,15 months group,with wild type mice with months as ck,using fluorescent immunohistochemical staining method to detect different weeks of AD rat fundus macrophages M1,M2,the expression of quantity and distribution characteristics,analysis of retinal inflammation changes in microenvironment and age-related.2.Optical coherence tomography(OCT)and immunohistofluorescence staining were used to observe the fundus expression of A in vivo and in vitro,and analyze the correlation with macrophage recruitment and trend distribution.3.Western blot and PCR were used to detect the expressions of INOS(M1),CD163(M2),A ? and mmp-9.4.A ? was used to co-culture with human and mouse RPE cells to construct cell models and verify the changes in biological functions and the expression of mmp-9.5.The RPE cell model was co-cultured with macrophages to verify the typing characteristics,migration and invasion changes of macrophages.Meanwhile,macrophage changes were observed after the expression of mmp-9 was down-regulated by siRNA.Results:the infiltration of macrophages in the fundus of AD model mice was significantly earlier than that of mice of the same age.In addition,M1-type macrophages were mainly found in the retina,and M2-type macrophages were mostly distributed in the choroid,indicating that the inflammatory microenvironment of fundus of AD model mice was changed earlier than that of normal mice.At the same time,the expression of A ? and the increase of mmp-9 in retina-choroid complex were found in each layer of retina.Through co-culture of the RPE cell model stimulated by A ? and macrophages,it was found that,while accelerating the senescence of RPE cells,A ? could rapidly induce the differentiation of macrophages in the M1-type direction.After down-regulating the expression of mmp-9,the differentiation of M1-type macrophages decreased,the overall activity of macrophages decreased,and the inflammation of fundus decreased,but the inflammation could not be completely eliminated.Conclusion:Alzheimer's disease-related A ? can be found in various layers of retina,and can promote the high expression of mmp-9 in retinal pigment epithelial cells.The increased mmp-9 and A ? directly/indirectly induced the differentiation of macrophages into Ml-type,changed the inflammatory microenvironment of the retina,and created conditions for the occurrence of age-related diseases of the fundus Inhibiting the high expression of mmp-9 will effectively improve the inflammatory microenvironment of retina and reduce the incidence of fundus diseases in alzheimer's disease patients.