ISU203 relieves Th17‐mediated neuroinflammation and facilitates removal of amyloid‐β plaques, resulting in the improved cognition in Alzheimer’s disease mouse model

Abstract

AbstractBackgroundAcid sphingomyelinase (ASM), which localized in endolysosome and plasma membrane, generates ceramide by hydrolyzing sphingomyelin. The enzymatic activity of ASM is elevated in elderly people. Interestingly, it was reported that the activity of ASM was significantly upregulated in patients with several inflammatory diseases, as well as Alzheimer’s disease (AD). Moreover, the inhibition of its activity by treatment of inhibitors or antibody ameliorates the AD pathologies, indicating that ASM is a feasible therapeutic target for AD.MethodTo understand the efficacy and mechanism of action, we administered ISU203 in AD mouse model (APP/PS1) via intraperitoneal injection at 50mg/kg, biw for 8 weeks. To evaluate the cognitive function, Morris Water Maze and Fear conditioning test were utilized. After behavioral tests, mice were sacrificed to demonstrate the deposition of amyloid‐β plaque and phagocytic function of microglia by using immunohistochemistry assay in cortex and hippocampus. To further investigates the neuroinflammation mediated by Th17, pro‐ and anti‐inflammatory gene levels were demonstrated by RT‐qPCR.ResultIn two behavioral tests, we found the improvement of cognitive function of ISU203‐treated group. Morris Water Maze test showed the declined escape latency time by 30%. Furthermore, it showed the significantly increased freezing ratio in ISU203‐treated group in fear conditioning test. ISU203‐treated group also showed alleviation of Th17‐mediated neuroinflammation. In line with this finding, pro‐inflammatory genes were downregulated. On the other hand, anti‐inflammatory genes were upregulated. In addition, we also found the decreased deposition of amyloid‐β plaques, which is an important pathological hallmark of AD. Furthermore, ISU203‐treated group showed that the more microglial cells were colocalized with amyloid‐β plaques, indicating the increased phagocytosis of amyloid‐β by microglia.ConclusionThe treatment of ISU203 showed the relief of Th17‐mediated neuroinflammation and enhanced the removal of amyloid‐β plaques by microglia in AD mouse model. As a result, ISU203 improves cognitive function, suggesting the ISU203 as a novel antibody therapeutics for AD.