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Pharmacological inhibition of CSF1R blocks microglial proliferation and prevents the progression of Alzheimer's-like pathology

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  • A. Olmos-Alonso
  • S. T. Schetters
  • S. Sri
  • K. Askew
  • M. Vargas-Caballero
  • C. Holscher
  • V. H. Perry
  • D. Gomez-Nicola
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<mark>Journal publication date</mark>08/2015
<mark>Journal</mark>Glia
Issue numberSuppl. 1
Volume63
Number of pages2
Pages (from-to)E346-E347
Publication statusPublished
Early online date15/06/15
Original languageEnglish
Event12th European Meeting on Glial Cell Function in Health and Disease - Bilbao, Spain
Duration: 15/07/201518/07/2015

Conference

Conference12th European Meeting on Glial Cell Function in Health and Disease
CountrySpain
Period15/07/1518/07/15

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 (AD). However, the study of microglial proliferation in AD and validation of the efficacy of CSF1R-inhibiting strategies has not yet been reported. In this study we found increased proliferation of microglial cells in human AD, in line with an increased upregulation of the CSF1Rdependent pro-mitogenic cascade, correlating with disease progression. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of Amyloid β (Aβ) 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 a shift in the microglial inflammatory profile to an antiinflammatory 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 Aβ plaques. Our results provide proof of the efficacy of CSF1R inhibition in a model of AD, 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.