The University of Southampton
University of Southampton Institutional Repository

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

Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology
Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology
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-? 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-? 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.
alzheimer’s disease, microglia, gliosis, neurodegeneration, inflammation
0006-8950
891-907
Olmos-Alonso, A.
c52c3bd9-2cf0-4b55-9214-cb549449db75
Schetters, S.T.T.
72245838-0027-473d-9de5-e8bab63fc30f
Sri, S.
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Askew, K.
ffc96fb4-f94c-4cb7-8479-e9f0b2dae0c7
Mancuso, R.
05786562-a993-4e37-926e-3c1fcf50b36d
Vargas-Caballero, M.
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Holscher, C.
e41acf22-216c-493a-be3a-01438fda7c43
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Gomez-Nicola, D.
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Olmos-Alonso, A.
c52c3bd9-2cf0-4b55-9214-cb549449db75
Schetters, S.T.T.
72245838-0027-473d-9de5-e8bab63fc30f
Sri, S.
ed51da26-76c4-45ff-95ab-5aa3bc7d7583
Askew, K.
ffc96fb4-f94c-4cb7-8479-e9f0b2dae0c7
Mancuso, R.
05786562-a993-4e37-926e-3c1fcf50b36d
Vargas-Caballero, M.
de2178ac-77fd-4748-9fe5-109ab8ad93e1
Holscher, C.
e41acf22-216c-493a-be3a-01438fda7c43
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Gomez-Nicola, D.
0680aa66-9dee-47cf-a8d3-e39c988f85b5

Olmos-Alonso, A., Schetters, S.T.T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V.H. and Gomez-Nicola, D. (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain, 139 (3), 891-907. (doi:10.1093/brain/awv379). (PMID:26747862)

Record type: Article

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-? 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-? 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.

Text Olmos-Alonso et al 2016.pdf - Version of Record
Available under License Creative Commons Attribution.
Download (2MB)

More information

Accepted/In Press date: 29 October 2015
Published date: 8 January 2016
Keywords: alzheimer’s disease, microglia, gliosis, neurodegeneration, inflammation
Organisations: Biomedicine

Identifiers

Local EPrints ID: 385694
URI: https://eprints.soton.ac.uk/id/eprint/385694
ISSN: 0006-8950
PURE UUID: 3ed4e976-edab-42b2-8727-c1e8d034db2f
ORCID for M. Vargas-Caballero: ORCID iD orcid.org/0000-0003-2326-4001
ORCID for D. Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

Catalogue record

Date deposited: 21 Jan 2016 11:15
Last modified: 06 Jun 2018 12:33

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×