TY - JOUR

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

AU - Olmos-Alonso, A.

AU - Schetters, S. T.

AU - Sri, S.

AU - Askew, K.

AU - Vargas-Caballero, M.

AU - Holscher, C.

AU - Perry, V. H.

AU - Gomez-Nicola, D.

PY - 2015/8

Y1 - 2015/8

N2 - The proliferation and activation of microglial cells is a hallmark of severalneurodegenerative 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.

AB - The proliferation and activation of microglial cells is a hallmark of severalneurodegenerative 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.

U2 - 10.1002/glia.22870

DO - 10.1002/glia.22870

M3 - Meeting abstract

VL - 63

SP - E346-E347

JO - Glia

JF - Glia

SN - 0894-1491

IS - Suppl. 1

T2 - 12th European Meeting on Glial Cell Function in Health and Disease

Y2 - 15 July 2015 through 18 July 2015

ER -