The Effect Of Simvastatin To The Appswe/PS1dE9 Transgenic Mouse With High Cholesterol Diet

Objective: Alzheimer's disease (AD) is a common neurodegenerative disease, which is characterized clinically by a progressive loss of memory and cognitive impairment. Its main pathogenesis include overproduction of extracellular amyloid (Aβ), neurofibrillary tangles and diffuse loss of neurons. Evidence from many recent studies has linked high cholesterol and AD, it's recognized that high cholesterol and high fat diet is a risk factor of AD. A latest study provides direct evidence that cholesterol homeostasis is impaired in AD brain and suggests that altered levels or activities of PPARγmay contribute to cholesterol retention which likely enhancesβ-andγ- secretase activities and Aβproduction. The purpose of this study is to clarify the role of cholesterol in the pathogenesis of AD and whether simvastatin have protection function of AD.Methods: We established the APPswe/PS1dE9 double transgenic mice model with different blood cholesterol levels:negative control group, negative control group with high fat diet , positive group with normal diet , positive drug group with normal diet , positive group with high fat diet , positive drug group with high fat diet. After 6 months high fat diet or normal diet, each group was given the cholesterol-lowing drug simvastatin (50mg/Kg) or placebo respectively for 3 months. Amyloid was detected by immunohistochemistry and thioflavin S; the expression of PPARγwas detected by RT-PCR and western blot.Results:1.This study established APPswe/PS1dE9 transgenic mice model with different cholesterol concentration.2.The results of immunohistochemistry and thioflavin S indicated that the group with high cholesterol diet showed more amount of Aβdisposition than normal diet, and the group treated with simvastatin showed less amount of Aβdisposition than placebo group. But the effect of simvastatin was not detected by Morris Water Maze.3.RT-PCR showed that there is no change in expression of PPARγ. Western blot indicated that the expression of PPARγin group treated with simvastatin were more than placebo group.Conclusions:1.High cholesterol diet may affect the amount of Aβdisposition, and simvastatin may reduce the amount of Aβdisposition.2.The expression of PPARγcan be activated by simvastatin.3.We speculate that the disposition of Aβcan be regulated by simvastatin. This response correlates with increasing expression of PPARγand succedent reducing of cholesterol concentration.