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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

PLX5622 inhibits chemotaxis of BV-2 cells in response to Aβ-oligomer-stimulated enriched media. Chemotaxis was measured by counting migrated BV2 cells in response to Aβ-stimulated enriched media or control enriched media. BV2 cells were treated with 0-, 1-, or 10 μM PLX5622 either 15 min or 24 h before the assay was conducted. All treated cells exhibited significantly reduced cell migration in response to the Aβ-stimulated enriched media
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Fig8: PLX5622 inhibits chemotaxis of BV-2 cells in response to Aβ-oligomer-stimulated enriched media. Chemotaxis was measured by counting migrated BV2 cells in response to Aβ-stimulated enriched media or control enriched media. BV2 cells were treated with 0-, 1-, or 10 μM PLX5622 either 15 min or 24 h before the assay was conducted. All treated cells exhibited significantly reduced cell migration in response to the Aβ-stimulated enriched media

Mentions: In order to determine the mechanism behind the reduced microglial association with Aβ plaques, we conducted a chemotaxis assay on BV2 microglial cells treated with 1- or 10 μM PLX5622 (equivalent to a low- and high-dose of PLX5622, respectively) for 15 min or 24 h (n = 5 per group). Aβ-oligomer-stimulated enriched BV2 media was used as a chemoattractant in a ChemoTx® Chemotaxis System, and chemotaxis was measured by BV2 cell migration towards the media. All treated groups with PLX5622 showed significantly reduced cell migration to the Aβ-enriched media, indicating an impaired ability to respond to the chemoattractant signals produced by Aβ-enriched BV2 media, supporting the lack of microglial association with plaques in the treated brain (Fig. 8).Fig. 8


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)

PLX5622 inhibits chemotaxis of BV-2 cells in response to Aβ-oligomer-stimulated enriched media. Chemotaxis was measured by counting migrated BV2 cells in response to Aβ-stimulated enriched media or control enriched media. BV2 cells were treated with 0-, 1-, or 10 μM PLX5622 either 15 min or 24 h before the assay was conducted. All treated cells exhibited significantly reduced cell migration in response to the Aβ-stimulated enriched media
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig8: PLX5622 inhibits chemotaxis of BV-2 cells in response to Aβ-oligomer-stimulated enriched media. Chemotaxis was measured by counting migrated BV2 cells in response to Aβ-stimulated enriched media or control enriched media. BV2 cells were treated with 0-, 1-, or 10 μM PLX5622 either 15 min or 24 h before the assay was conducted. All treated cells exhibited significantly reduced cell migration in response to the Aβ-stimulated enriched media
Mentions: In order to determine the mechanism behind the reduced microglial association with Aβ plaques, we conducted a chemotaxis assay on BV2 microglial cells treated with 1- or 10 μM PLX5622 (equivalent to a low- and high-dose of PLX5622, respectively) for 15 min or 24 h (n = 5 per group). Aβ-oligomer-stimulated enriched BV2 media was used as a chemoattractant in a ChemoTx® Chemotaxis System, and chemotaxis was measured by BV2 cell migration towards the media. All treated groups with PLX5622 showed significantly reduced cell migration to the Aβ-enriched media, indicating an impaired ability to respond to the chemoattractant signals produced by Aβ-enriched BV2 media, supporting the lack of microglial association with plaques in the treated brain (Fig. 8).Fig. 8

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