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

Olmos-Alonso, A. and Schetters, S. T. and Sri, S. and Askew, K. and Vargas-Caballero, M. and Holscher, C. and Perry, V. H. and Gomez-Nicola, D. (2015) Pharmacological inhibition of CSF1R blocks microglial proliferation and prevents the progression of Alzheimer's-like pathology. Glia, 63 (Suppl.). E346-E347. ISSN 0894-1491

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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.

Item Type:
Journal Article
Journal or Publication Title:
Glia
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2800/2808
Subjects:
ID Code:
76716
Deposited By:
Deposited On:
17 Nov 2015 16:02
Refereed?:
Yes
Published?:
Published
Last Modified:
10 Sep 2020 02:38