Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology

Brain. 2016 Mar;139(Pt 3):891-907. doi: 10.1093/brain/awv379. Epub 2016 Jan 8.

Abstract

The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease.

Keywords: Alzheimer’s disease; gliosis; inflammation; microglia; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / prevention & control*
  • Animals
  • Anisoles / administration & dosage
  • Cell Proliferation / drug effects*
  • Cell Proliferation / physiology
  • Disease Progression*
  • Drug Delivery Systems* / methods
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Plaque, Amyloid / prevention & control
  • Protein Kinase Inhibitors / administration & dosage
  • Pyrimidines / administration & dosage
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism

Substances

  • 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine
  • Anisoles
  • Csf1r protein, mouse
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor