1. Reduced Smoothened level rescues Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease
- Author
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Mengnan Wu, Wei-Wei Ma, Yi Zhong, Ye Tao, Siyan Zhou, and Zuolei Xie
- Subjects
0301 basic medicine ,Genetically modified mouse ,Amyloid beta ,Morris water navigation task ,Down-Regulation ,Inflammation ,03 medical and health sciences ,Mice ,Cognition ,Downregulation and upregulation ,Alzheimer Disease ,Genetics ,medicine ,Animals ,Molecular Biology ,Neurons ,Memory Disorders ,Amyloid beta-Peptides ,biology ,Microglia ,medicine.disease ,Smoothened Receptor ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Mutation ,biology.protein ,Cancer research ,medicine.symptom ,Alzheimer's disease ,Smoothened ,Signal Transduction - 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 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.
- Published
- 2017