Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease

查看全文 作　　者：Weiwei [1]Ma;Mengnan [1]Wu;Siyan [1]Zhou;Ye [2]Tao;Zuolei [3]Xie;Yi [1]Zhong

机构地区：[1]School of Life Sciences,Tsinghua University,Beijing 100084,China;[2]Suzhou Joekai Biotechnology LLC Suzhou 215347,China;[3]Beijing Joekai Biotechnology LLC,Beijing 100094,China

出　　处：《Journal of Genetics and Genomics》索引2018年第45卷第5期,共10页

基　　金：supported by grants from the National Science Foundation of China(Nos.91332207 and 91632301,to Yi Zhong);the Beijing Municipal Science and Technology Commission(Z161100002616010,to Yi Zhong);the National Basic Research Project(973 program)of the Ministry of Science and Technology of China(2013cb835100,to Yi Zhong);the Tsinghua-Peking Joint Center for Life Sciences 摘　　要：Emerging evidence suggests that neuro-inflammation begins early and drives the pathogenesis of Alzheimer's disease(AD), and anti-inflammatory therapies are under clinical development. However,several anti-inflammatory compounds failed to improve memory in clinical trials, indicating that reducing inflammation alone might not be enough. On the other hand, neuro-inflammation is implicated in a number of mental disorders which share the same therapeutic targets. Based on these observations,we screened a batch of genes related with mental disorder and neuro-inflammation in a classical olfactory conditioning in an amyloid beta(Aβ) overexpression fly model. A Smoothened(SMO) mutant was identified as a genetic modifier of Aβ toxicity in 3-min memory and downregulation of SMO rescued Aβ induced 3-min and 1-h memory deficiency. Also, Aβ activated innate inflammatory response in fly by increasing the expression of antimicrobial peptides, which were alleviated by downregulating SMO.Furthermore, pharmaceutical administration of a SMO antagonist LDE rescued Aβ-induced upregulation of SMO in astrocytes of mouse hippocampus, improved memory in Morris water maze(MWM), and reduced expression of astrocyte secreting pro-inflammatory factors IL-1 b, TNFa and the microglia marker IBA-1 in an APP/PS1 transgenic mouse model. Our study suggests that SMO is an important conserved modulator of Aβ toxicity in both fly and mouse models of AD. 关键词：动物模型水迷宫记忆疾病营救苍蝇模型基因修饰 SMO

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Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease

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