The Mechanisms And Therapeutic Strategies To The Region-selected Damage Of Alzheimer's Disease

ObjectivesTo investigate the effect and the underlying mechanisms of Metabolites of Cerebellar Neurons on the contents and deposition of beta-amyloid (Aβ) in cerebral cortex and hippocampus in rats and APP/PS1 transgenic mice; And to investigate the effect and mechanisms of the difference of PPARγactivity on the Region-Selected Damage of Alzheimer's Disease , which bring a new insight to the possible treatment of Alzheimer's DiseaseMethodsCerebellum conditioned medium or cerebrospinal fluid drawn from the fourth ventricle was injected into the lateral ventricle of the rats or APP/PS1 transgenic mice, guided by stereotaxic apparatus. Contents, as well as the deposition of Aβin cerebral cortex and hippocampus were determined by Enzyme Linked Immunosorbent Assay (ELISA),Fluorence Staining and Immunohistochemistry techniques. Western blotting was also employed to detect Insulin-Degrading Enzyme (IDE) and Neprilysin (NEP) expression in cerebral cortex.GW9662, an antagonist of PPARγ, was injected into the fourth ventricle of the APP/PS1 transgenic mice, guided by stereotaxic apparatus. Contents, as well as the deposition of Aβin cerebellum were determined by Enzyme Linked Immunosorbent Assay (ELISA),Fluorence Staining and Immunohistochemistry techniques. Western blotting was also employed to detect Insulin-Degrading Enzyme(IDE)expression in cerebellum.ResultsMetabolites of Cerebellar Neurons could reduce the deposition of both soluble and insoluble Aβin cerebral cortex and the hippocampus in rats and APP/PS1 transgenic mice, and Metabolites of Cerebellar Neurons could also attenuate cognitive impairments of APP/PS1 transgenic mice. Meanwhile, the expression of Insulin Degrading Enzyme (IDE) and Neprilysin (NEP) which mediates the proteolysis of extracellular Aβwas up-regulated simultaneously in cerebral cortex and hippocampus.GW9662, an antagonist of PPARγ, could increase the deposition of both soluble and insoluble Aβin cerebellum in APP/PS1 transgenic mice. GW9662 could also induce cerebellar motor dysfunction in APP/PS1 transgenic mice. Meanwhile, the expression of Insulin Degrading Enzyme (IDE) which mediates the proteolysis of extracellular Aβwas down-regulated simultaneously in cerebellum.ConclusionMetabolites of Cerebellar Neurons could reduce the abnormal deposition of Aβin cerebral cortex and hippocampus through up-regulating the expression of IDE and NEP. Moreover, the high activity of PPARγi?n cerebellum can help to resist AD pathology b?y up-regulating the expression of IDE t?o degrade A?β. This study might bring a new insight to the possible clinical treatment of Alzheimer's Disease.