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

Weiwei Ma; Mengnan Wu; Siyan Zhou; Ye Tao; Zuolei Xie; Yi Zhong

doi:10.1016/j.jgg.2018.05.001

Volume 45 Issue 5

May 2018

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Article Navigation > Journal of Genetics and Genomics > 2018 > 45(5): 237-246

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

doi: 10.1016/j.jgg.2018.05.001

a
School of Life Sciences, Tsinghua University, Beijing 100084, China
b
Suzhou Joekai Biotechnology LLC, Suzhou 215347, China
c
Beijing Joekai Biotechnology LLC, Beijing 100094, China

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Corresponding 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.
- Alzheimer disease,
- Inflammation,
- Learning and memory,
- Smoothened

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References(51)

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