title: Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.
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.
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Olmos-Alonso
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Sjoerd T T
authors.initials: ST
authors.lastname: Schetters
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Sarmi
authors.initials: S
authors.lastname: Sri
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Askew
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: Renzo
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK 2 Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: Mariana
authors.initials: M
authors.lastname: Vargas-Caballero
authors.affiliation: 3 Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Holscher
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK.
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.affiliation: 1 Centre for Biological Sciences, University of Southampton, Southampton, UK d.gomez-nicola@soton.ac.uk.
authors.forename: Diego
authors.initials: D
authors.lastname: Gomez-Nicola
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D018450:Disease Progression; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; C000604004:Csf1r protein, mouse; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Alzheimer’s disease; gliosis; inflammation; microglia; neurodegeneration