Mengnan Wu
Siyan Zhou
Ye Tao
Zuolei Xie
Yi Zhong
aSchool of Life Sciences, Tsinghua University, Beijing 100084, China
bSuzhou Joekai Biotechnology LLC, Suzhou 215347, China
cBeijing Joekai Biotechnology LLC, Beijing 100094, China
More InformationCorresponding author: E-mail address: zhongyi@mail.tsinghua.edu.cn (Yi Zhong)
Received Date: 2017-11-27
Accepted Date:2018-05-07
Rev Recd Date:2018-05-06
Available Online: 2018-05-09 Publish Date:2018-05-20
Abstract
Abstract
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-1β, TNFα and the microglia marker IBA-1 in anAPP/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.Keywords: Alzheimer disease,
Inflammation,
Learning and memory,
Smoothened
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