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

Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, West BL, Green KN - J Neuroinflammation (2015)

Bottom Line: 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.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.We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, 3208 Biological Sciences III, Irvine, CA, 92697-4545, USA. ndagher53@gmail.com.

ABSTRACT

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 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.

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 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.

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.

No MeSH data available.


Related in: MedlinePlus

CSF1R inhibition does not alter cognition or behavior in adult mice. a Two-month-old wild-type mice were treated with either vehicle, 300 or 1200 mg/kg PLX5622 for 14 days, and behavioral analyses were conducted using an open-field test and Barnes maze. b–e No differences were measured across groups in the open-field test in distance traveled, velocity, time spent in open arena, or time spent in edge of arena. f–g No differences were measured across groups in the Barnes maze in acquisition of time to find escape hole or in probe trial. Error bars indicate SEM
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Fig2: CSF1R inhibition does not alter cognition or behavior in adult mice. a Two-month-old wild-type mice were treated with either vehicle, 300 or 1200 mg/kg PLX5622 for 14 days, and behavioral analyses were conducted using an open-field test and Barnes maze. b–e No differences were measured across groups in the open-field test in distance traveled, velocity, time spent in open arena, or time spent in edge of arena. f–g No differences were measured across groups in the Barnes maze in acquisition of time to find escape hole or in probe trial. Error bars indicate SEM

Mentions: Two-month-old wild-type mice were treated with either vehicle or 300- or 1200 mg/kg chow PLX5622 for 14 days, and behavioral analyses were then conducted (n = 10 per group) (Fig. 2a–g). Mice were first tested in open field analyses. No differences were seen in mice with either dose of PLX5622 in the distance traveled (Fig. 2b), velocity (Fig. 2c), time spent in the open area (Fig. 2d), or time spent in the edge of the arena (Fig. 2e), compared to vehicle-treated mice. Next, mice were tested on Barnes maze—a hippocampal-dependent learning and memory task. Again, no differences were found between any of the groups on acquisition of the time to find the escape hole (Fig. 2f) or in the probe trial conducted 24 h after the last training session (Fig. 2g). Thus, depletion of microglia with PLX5622 does not induce any deficits in these particular tasks, in agreement with our previous data [6].Fig. 2


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

Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, West BL, Green KN - J Neuroinflammation (2015)

CSF1R inhibition does not alter cognition or behavior in adult mice. a Two-month-old wild-type mice were treated with either vehicle, 300 or 1200 mg/kg PLX5622 for 14 days, and behavioral analyses were conducted using an open-field test and Barnes maze. b–e No differences were measured across groups in the open-field test in distance traveled, velocity, time spent in open arena, or time spent in edge of arena. f–g No differences were measured across groups in the Barnes maze in acquisition of time to find escape hole or in probe trial. Error bars indicate SEM
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522109&req=5

Fig2: CSF1R inhibition does not alter cognition or behavior in adult mice. a Two-month-old wild-type mice were treated with either vehicle, 300 or 1200 mg/kg PLX5622 for 14 days, and behavioral analyses were conducted using an open-field test and Barnes maze. b–e No differences were measured across groups in the open-field test in distance traveled, velocity, time spent in open arena, or time spent in edge of arena. f–g No differences were measured across groups in the Barnes maze in acquisition of time to find escape hole or in probe trial. Error bars indicate SEM
Mentions: Two-month-old wild-type mice were treated with either vehicle or 300- or 1200 mg/kg chow PLX5622 for 14 days, and behavioral analyses were then conducted (n = 10 per group) (Fig. 2a–g). Mice were first tested in open field analyses. No differences were seen in mice with either dose of PLX5622 in the distance traveled (Fig. 2b), velocity (Fig. 2c), time spent in the open area (Fig. 2d), or time spent in the edge of the arena (Fig. 2e), compared to vehicle-treated mice. Next, mice were tested on Barnes maze—a hippocampal-dependent learning and memory task. Again, no differences were found between any of the groups on acquisition of the time to find the escape hole (Fig. 2f) or in the probe trial conducted 24 h after the last training session (Fig. 2g). Thus, depletion of microglia with PLX5622 does not induce any deficits in these particular tasks, in agreement with our previous data [6].Fig. 2

Bottom Line: 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.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.We find that inhibition of CSF1R alone is sufficient to eliminate microglia and that sustained microglial elimination is concentration-dependent.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, 3208 Biological Sciences III, Irvine, CA, 92697-4545, USA. ndagher53@gmail.com.

ABSTRACT

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 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.

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 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.

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.

No MeSH data available.


Related in: MedlinePlus