TIPE2,A Negative Regulator Of Innate And Adaptive Immunity,Attenuates Cognitive Deficits In APP/PS1 Mice And Its Mechanism

Objective: Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease(AD).Tumor necrosis factor-?-induced protein 8-like 2(TIPE2)has been identified as a negative regulator of innate and adaptive immun response.However,whether TIPE2 was involved in the pathogenesis of AD remains unknown.The purpose of this study is to explore whether TIPE2 is involved in the pathological process of AD and its possible mechanism.Methods: 1.This study compared behavioral changes in APP/PS1 transgenic mice and wild-type(WT)mice of the same age during development using the fear condition test and the Y-maze behavioral evaluation method for learning and memory.2.Immunofluorescence was used to detect the amyloid beta protein deposition in the brain of APP/PS1 transgenic mice during development.3.TIPE2 gene and protein expressionin in the brain of APP/PS1 transgenic mice during development were detected by q PCR and western blot.4.Intracerebral injection of adeno-associated virus induced high expression of TIPE2 in hippocampus of APP/PS1 transgenic mice.To observe the effect of high expression of TIPE2 on behavior of APP/PS1 transgenic mice.5.To detect the effect of TIPE2 overexpression on the expression of inflammatory factors in APP/PS1 mice brain by q PCR and western blot.6.Immunofluorescence was used to detect the effect of TIPE2 on the microglia in the brain of APP/PS1 transgenic mice.Results: 1.APP/PS1 transgenic mice showed significant cognitive deficits in the Y-maze test and the conditional fear test from 8-month old,and the more obvious the cognitive deficits were with the increase of age.2.A? deposition began to appear in the hippocampus of APP/PS1 transgenic mice from 6-month old,and it began to appear in the cerebral cortex from 8-month old,while no deposition of A? was detected in WT mice of any age.3.From 6-month old,the expression of TIPE2 m RNA and protein in hippocampus of APP/PS1 transgenic mice was higher than that of WT mice of the same age.The difference between APP/PS1 mice and WT mice gradually decreased after 8-month old,and disappeared at 12-month old.From the age of 7-month old,the expression of TIPE2 m RNA and protein in the cerebral cortex of APP/PS1 transgenic mice was significantly higher than that of WT mice of the same age,and then the difference between APP/PS1 mice and WT mice gradually decreased.By 12-month old,the difference between the two groups disappeared.4.Overexpression of TIPE2 in the hippocampus of 7-month-old APP/PS1 transgenic mice effectively improved cognitive deficits.This effect last for at least 3.5 months 5.Overexpression of TIPE2 in the brain of APP/PS1 transgenic mice reduced inflammatory factors such as TNF-?,IL-6 and IL-1?,and increased the anti-inflammatory factors IL-10 and Arg-1.6.Overexpression of TIPE2 in the brain of APP/PS1 transgenic mice reversed morphological changes and dysfunction of microglia.Conclusions: 1.The expression of TIPE2 in the brain of APP/PS1 transgenic mice was negatively correlated with the learning and cognitive abilities of mice.2.Overexpression of TIPE2 in the brain of APP/PS1 transgenic mice can effectively improve cognitive deficits.3.Overexpression of TIPE2 in the brain of APP/PS1 transgenic mice significantly reduced the level of inflammation,increased the anti-inflammatory levels in the brain,indicating TIPE2 is a potential target for drug intervention and improvement of cognitive deficits...