Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice

Background: microglia are dependent upon colony-stimulating factor 1 receptor (csf1r) signaling for their survival in the adult brain,with administration of the dual csf1r/c-kit inhibitor plx3397 leading to the near-complete elimination of all microglia brainwide. here,we determined the dose-dependent effects of a specific csf1r inhibitor (plx5622) on microglia in both wild-type and the 3xtg-ad mouse model of alzheimer's disease. methods: wild-type mice were treated with plx5622 for up to 21days,and the effects on microglial numbers were assessed. 3xtg-ad mice were treated with plx5622 for 6 or 12weeks and effects on microglial numbers and pathology subsequently assessed. results: high doses of csf1r inhibitor eliminate most microglia from the brain,but a 75% lower-dose results in sustained elimination of ~30% of microglia in both wild-type and 3xtg-ad mice. no behavioral or cognitive deficits were found in mice either depleted of microglia or treated with lower csf1r inhibitor concentrations. aged 3xtg-ad mice treated for 6 or 12weeks with lower levels of plx5622 resulted in improved learning and memory. aβ levels and plaque loads were not altered,but microglia in treated mice no longer associated with plaques,revealing a role for the csf1r in the microglial reaction to plaques,as well as in mediating cognitive deficits. conclusions: we find that inhibition of csf1r alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent. inhibition of the csf1r at lower levels in 3xtg-ad mice prevents microglial association with plaques and improves cognition. © 2015 dagher et al.