title: Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice.
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.
authors.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.
authors.forename: Nabil N
authors.initials: NN
authors.lastname: Dagher
authors.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. haskella@uci.edu.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Najafi
authors.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. kara.kayala@gmail.com.
authors.forename: Kara M Neely
authors.initials: KM
authors.lastname: Kayala
authors.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. elmorem@uci.edu.
authors.forename: Monica R P
authors.initials: MR
authors.lastname: Elmore
authors.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. tewhite@uci.edu.
authors.forename: Terra E
authors.initials: TE
authors.lastname: White
authors.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. rodrigo.medeiros@uci.edu.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Plexxikon Inc., Berkeley, CA, USA. bwest@plexxikon.com.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.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. kngreen@uci.edu.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology*; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001921:Brain / Q000187:drug effects; D002452:Cell Count; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D058225:Plaque, Amyloid / Q000473:pathology*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*
chemical_list: C000604004:Csf1r protein, mouse; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor