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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

Lower-dose CSF1R inhibition does not alter Aβ or Tau levels. a, b Sandwich ELISA in soluble and insoluble fraction revealed no significant differences in Aβ40 or Aβ42 between groups. c, d Thioflavin-S staining was performed, revealing plaques in both control and treated groups. Of the subiculum, 10× images are shown. e–g Analysis of plaques revealed no significant difference between treated and untreated brains in average number of plaques, average plaque size, or distribution of large, medium, and small plaques. h–k Immunostaining for total human tau with HT7 (h, i) and AT8 tau (j, k) reveals no significant differences in tau levels with PLX5622 treatment. Error bars indicate SEM
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Fig6: Lower-dose CSF1R inhibition does not alter Aβ or Tau levels. a, b Sandwich ELISA in soluble and insoluble fraction revealed no significant differences in Aβ40 or Aβ42 between groups. c, d Thioflavin-S staining was performed, revealing plaques in both control and treated groups. Of the subiculum, 10× images are shown. e–g Analysis of plaques revealed no significant difference between treated and untreated brains in average number of plaques, average plaque size, or distribution of large, medium, and small plaques. h–k Immunostaining for total human tau with HT7 (h, i) and AT8 tau (j, k) reveals no significant differences in tau levels with PLX5622 treatment. Error bars indicate SEM

Mentions: Sandwich ELISA for Aβ40 and Aβ42 in the soluble and insoluble fractions revealed no significant differences between the PLX5622-treated group and the controls (Fig. 6a, b). Thio-S staining revealed abundant dense core plaques in all animals, particularly in the subiculum (Fig. 6c, d). Quantification of number of plaques (Fig. 6e), average plaque size (Fig. 6f), or distribution of small, medium, or large plaques (Fig. 6g), revealed no changes with treatment.Fig. 6


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)

Lower-dose CSF1R inhibition does not alter Aβ or Tau levels. a, b Sandwich ELISA in soluble and insoluble fraction revealed no significant differences in Aβ40 or Aβ42 between groups. c, d Thioflavin-S staining was performed, revealing plaques in both control and treated groups. Of the subiculum, 10× images are shown. e–g Analysis of plaques revealed no significant difference between treated and untreated brains in average number of plaques, average plaque size, or distribution of large, medium, and small plaques. h–k Immunostaining for total human tau with HT7 (h, i) and AT8 tau (j, k) reveals no significant differences in tau levels with PLX5622 treatment. 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

Fig6: Lower-dose CSF1R inhibition does not alter Aβ or Tau levels. a, b Sandwich ELISA in soluble and insoluble fraction revealed no significant differences in Aβ40 or Aβ42 between groups. c, d Thioflavin-S staining was performed, revealing plaques in both control and treated groups. Of the subiculum, 10× images are shown. e–g Analysis of plaques revealed no significant difference between treated and untreated brains in average number of plaques, average plaque size, or distribution of large, medium, and small plaques. h–k Immunostaining for total human tau with HT7 (h, i) and AT8 tau (j, k) reveals no significant differences in tau levels with PLX5622 treatment. Error bars indicate SEM
Mentions: Sandwich ELISA for Aβ40 and Aβ42 in the soluble and insoluble fractions revealed no significant differences between the PLX5622-treated group and the controls (Fig. 6a, b). Thio-S staining revealed abundant dense core plaques in all animals, particularly in the subiculum (Fig. 6c, d). Quantification of number of plaques (Fig. 6e), average plaque size (Fig. 6f), or distribution of small, medium, or large plaques (Fig. 6g), revealed no changes with treatment.Fig. 6

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