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

Abstract

BackgroundMicroglia 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.MethodsWild-type mice were treated with PLX5622 for up to 21 days, and the effects on microglial numbers were assessed. 3xTg-AD mice were treated with PLX5622 for 6 or 12 weeks and effects on microglial numbers and pathology subsequently assessed.ResultsHigh 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 12 weeks 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.ConclusionsWe 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.

Microglia ablation alleviates myelin-associated catatonic signs in mice

“…After 5 and 8 weeks of PLX5622, catatonic signs were reduced ( Figure 4B). In agreement with the literature, PLX5622-treated WT mice were almost completely depleted of Iba1 + cells (22,23), even though -compared with young mice -around 10 times more microglial cells/mm 2 corpus callosum area were retained. In contrast, Cnp -/-mice showed substan- .…”

“…Catatonic signs were prevented by a 5-week oral application of the CSF1R inhibitor PLX5622 via food pellets, starting at 3 weeks of age, immediately after weaning ( Figure 2, C and D), consistent with a nearly complete depletion of microglia as reported earlier (22,23) and reproduced by pilot experiments in preparation of the present study (8- Figure 2E). Intriguingly, immunohistochemical (IHC) analysis of the corpus callosum of these mice after 4 weeks of drug recovery showed still lower numbers of Iba1 ; P < 0.014) in young mutants is not reduced after PLX5622 treatment.…”

“…PLX5622 (formulated in AIN-76A standard chow by Research Diets; 1,200 ppm) and control food (AIN-76A) were provided by Plexxikon Inc. (22,23). For tracking of potential batch-tobatch variations in future studies, PLX5622 lot numbers are given: 17032710A5TT1.0i; 16010809A9TT1.0i; 17010309A7TT1.0i; and 16092608A1TT1.0i.…”

“…The first MRS in 8-week-old mice was performed after 5 weeks of control versus PLX5622 diet (starting at age 3 weeks, as in the prevention study above), and the second MRS was performed in the same mice at the age of 13 weeks, i.e., after 5 weeks of PLX5622 food cessation/microglia repopulation. Brain myoinositol is seen as a global marker of glial activation including microglia that strongly correlates with neuroinflaminhibitor PLX5622 (22,23), which blocks a critical microglial survival pathway. The so-caused ablation of microglia prevents catatonia onset in young mutants and ameliorates existing catatonia in adult Cnp -/-mice.…”

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

“…We identified several orally bioavailable CSF1R inhibitors that noninvasively cross the blood‐brain barrier, leading to brain‐wide microglial elimination within days, which continues for as long as CSF1R inhibition is present (Dagher et al, 2015; Elmore et al, 2014). In particular, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells (Elmore et al, 2014; Elmore, Lee, West, & Green, 2015; Rice et al, 2017), effectively replacing the entire microglial tissue.…”