The Regulation Of Insulin-degrading Enzyme Expression And Application In Alzheimer's Disease

As the development of worldwide aging society, Alzheimer's disease (AD) has become an unneglectable sanitary and social problem which threatens human health all over the world. According to the amyloid hypothesis, the cause of AD isβ-amyloid (Aβ) deposition in brain. The regional specific deposition of Aβand neurotoxicity in some brain regions including hippocampus and cerebral cortex, is an important character of AD. However, other brain regions including cerebellum, are spared from significant Aβaccumulation. The investigation of the mechanism underlying this regional specificity is crucial for the understanding of AD pathology. In the present study, through bioinformatics and molecular biological methods including chromatin immunoprecipitation, we demonstrated that the expression of insulin-degrading enzyme (IDE), an important enzyme responsible for Aβdegradation, was regulated by peroxisome proliferator-activated receptorγ(PPARγ). Moreover, IDE expression level and PPARγactivity are selectively down-regulated in hippocampus and cerebral cortex, compared with cerebellum. The high level of PPARγ-IDE pathway contributed to the resistance of cerebellum to AD pathology in AD transgenic mice. Furthermore, we found that the metabolites of cerebellar neurons significantly induced IDE expression in hippocampus and decreased hippocampal Aβlevels and ameliorated the learning and memory deficits of AD transgenic mice. In addition, we found ApoE4, a risk factor of AD, significantly reduced IDE expression in hippocampal neurons, probably through activating the NMDA receptor. Moreover, transfection of human ApoE3, but not ApoE4, rescued the reduced IDE level in hippocampal neurons from apoe knockout mice. Finally, we demonstrated that the expression of IDE in neurons also regulated by nerve growth factor (NGF). Injection of NGF into the lateral ventricles of SD rats significantly up-regulated the expression of IDE, while deprivation of NGF by its specific antibody reduced IDE levels in brain. Taken together, our study revealed the mechanism underlying the regulation of IDE expression in brain and the possible application in AD pathology. These findings provide a novel clue for the understanding of AD pathology and new targets for AD therapy.