Accumulation of soluble, oligomeric amyloid-β (oAβ) species in the brain is one of the main hallmarks of Alzheimer´s disease (AD) and occurs early during disease pathogenesis. Several studies have shown that microglia are observed surrounding Aβ plaques contributing to the development of the disease. Microglia are inefficient at degrading fibrillar Aβ unless activated by immunotherapy or other methods. There is currently limited knowledge on the effect of macrophage colony-stimulating factor (MCSF)on microglial gene expression, microglial Aβ clearance surveillance, and synapse pathology. Given the importance of the MCSF/CSF-1R signaling axis, we hypothesize that this pathway can be used to enhance microglial degradation of Aβ and therefore in the treatment of AD. In order to investigate this hypothesis, we have characterized the effects of MCSF activation of microglia in vitro, ex vivo and in vivo in different of models of AD. Overall, our results provide evidence supporting that MCSF promotes a more efficient and protective microglia phenotype against Aβ in AD models.