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

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Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. / Olmos-Alonso, Adrian; Schetters, Sjoerd T. T.; Sri, Sarmi et al.
In: Brain, Vol. 139, No. 3, 01.03.2016, p. 891-907.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Olmos-Alonso, A, Schetters, STT, Sri, S, Askew, K, Mancuso, R, Vargas-Caballero, M, Holscher, C, Perry, VH & Gomez-Nicola, D 2016, 'Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology', Brain, vol. 139, no. 3, pp. 891-907. https://doi.org/10.1093/brain/awv379

APA

Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & 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. https://doi.org/10.1093/brain/awv379

Vancouver

Olmos-Alonso A, Schetters STT, Sri S, Askew K, Mancuso R, Vargas-Caballero M et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain. 2016 Mar 1;139(3):891-907. Epub 2016 Jan 8. doi: 10.1093/brain/awv379

Author

Olmos-Alonso, Adrian ; Schetters, Sjoerd T. T. ; Sri, Sarmi et al. / Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. In: Brain. 2016 ; Vol. 139, No. 3. pp. 891-907.

Bibtex

@article{c89bef0c44ec446cad4d04c0ca9ce110,
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. ",
keywords = "Alzheimer{\textquoteright}s disease, microglia, gliosis, inflammation, neurodegeneration",
author = "Adrian Olmos-Alonso and Schetters, {Sjoerd T. T.} and Sarmi Sri and Katharine Askew and Renzo Mancuso and Mariana Vargas-Caballero and Christian Holscher and Perry, {V. Hugh} and Diego Gomez-Nicola",
year = "2016",
month = mar,
day = "1",
doi = "10.1093/brain/awv379",
language = "English",
volume = "139",
pages = "891--907",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "3",

}

RIS

TY - JOUR

T1 - Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology

AU - Olmos-Alonso, Adrian

AU - Schetters, Sjoerd T. T.

AU - Sri, Sarmi

AU - Askew, Katharine

AU - Mancuso, Renzo

AU - Vargas-Caballero, Mariana

AU - Holscher, Christian

AU - Perry, V. Hugh

AU - Gomez-Nicola, Diego

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - microglia

KW - gliosis

KW - inflammation

KW - neurodegeneration

U2 - 10.1093/brain/awv379

DO - 10.1093/brain/awv379

M3 - Journal article

VL - 139

SP - 891

EP - 907

JO - Brain

JF - Brain

SN - 0006-8950

IS - 3

ER -