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

J Genet Genomics. 2018 May 20;45(5):237-246. doi: 10.1016/j.jgg.2018.05.001. Epub 2018 May 9.


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.

Keywords: Alzheimer disease; Inflammation; Learning and memory; Smoothened.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Cognition / drug effects
  • Disease Models, Animal
  • Down-Regulation / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / metabolism*
  • Memory Disorders / pathology*
  • Memory Disorders / physiopathology
  • Mice
  • Mutation
  • Neurons / drug effects*
  • Neurons / pathology
  • Signal Transduction / drug effects
  • Smoothened Receptor / genetics
  • Smoothened Receptor / metabolism*


  • Amyloid beta-Peptides
  • Smoothened Receptor