Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency

Neurobiol Aging. 2013 Dec;34(12):2843-52. doi: 10.1016/j.neurobiolaging.2013.06.003. Epub 2013 Jul 12.

Abstract

The abnormal accumulation of amyloid fibrils in the brain is pathognomonic of Alzheimer's disease. Amyloid fibrils induce significant neuroinflammation characterized by the activation of microglia and impairment of synaptic plasticity in the brain that eventually leads to cognitive decline. Chemokine fractalkine receptor (CX3CR1) is primarily located in the microglia in the brain and its role in the amyloid fibril-induced neuroinflammation and memory deficiency remains debated. We found that bilateral microinjection of amyloid beta (Aβ)1-40 fibrils into the hippocampal CA1 area of rats resulted in significant upregulation of CX3CR1 messenger RNA (mRNA) and protein expression (via increasing histone H3 acetylation in the Cx3cr1 promoter region), synaptic dysfunction, and cognitive impairment, compared with the control group. Suppressing CX3CR1 signaling with CX3CR1 small interfering RNA in rats injected with Aβ1-40 fibrils blunted Aβ1-40-induced CX3CR1 upregulation, microglial activation, interleukin-1β expression, restored basal glutamatergic strength and electric stimuli-induced long-term potentiation, and cognitive capacities. These findings suggest that activation of CX3CR1 plays an important role in the neuroinflammatory response and Aβ-induced neuroinflammation and neurotoxicity.

Keywords: Alzheimer's disease; Amyloid; CX3CR1; Hippocampus; Histone acetylation; Microglia.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / etiology*
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / toxicity
  • Animals
  • CA1 Region, Hippocampal
  • CX3C Chemokine Receptor 1
  • Depression, Chemical
  • Disease Models, Animal
  • Gene Expression
  • Male
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology*
  • Microinjections
  • Neuronal Plasticity / drug effects
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / toxicity
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / pharmacology*
  • RNA, Small Interfering / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Receptors, Chemokine / physiology
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Synapses / drug effects
  • Synapses / physiology
  • Up-Regulation / drug effects

Substances

  • Amyloid beta-Peptides
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, rat
  • Peptide Fragments
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Chemokine
  • amyloid beta-protein (1-40)