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

作　　者：Weiwei Ma Mengnan Wu Siyan Zhou Ye Tao Zuolei Xie Yi 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》2018年第5期237-246,共10页遗传学报（英文版）

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 ofastrocyte secreting pro-inflammatory factors IL-1β, TNFα 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 flv and mouse models of AD.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 ofastrocyte secreting pro-inflammatory factors IL-1β, TNFα 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 flv and mouse models of AD.

关 键 词：Alzheimer disease INFLAMMATION Learning and memory SMOOTHENED 

分 类 号：R-332[医药卫生] R749.16