title: Attenuation of microglial activation in a mouse model of Alzheimer's disease via NFAT inhibition.
abstract: BACKGROUND
  Amyloid β (Aβ) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer's disease (AD) brains. The specific mechanisms by which Aβ leads to microglial activation remain an area of interest for identifying attractive molecular targets for intervention. Based upon the fact that microglia express the proinflammatory transcription factor, nuclear factor of activated T cells (NFAT), we hypothesized that NFAT activity is required for the Aβ-stimulated microgliosis that occurs during disease.
  
  
  METHODS
  Primary murine microglia cultures were stimulated with Aβ in the absence or presence of NFAT inhibitors, FK506 and tat-VIVIT peptide, to quantify secretion of cytokines, neurotoxins, or Aβ phagocytosis. A transgenic mouse model of AD, APP/PS1, was treated subcutaneously via mini-osmotic pumps with FK506 or tat-VIVIT to quantify effects on cytokines, microgliosis, plaque load, and memory.
  
  
  RESULTS
  Expression of various NFAT isoforms was verified in primary murine microglia through Western blot analysis. Microglial cultures were stimulated with Aβ fibrils in the absence or presence of the NFAT inhibitors, FK506 and tat-VIVIT, to demonstrate that NFAT activity regulated Aβ phagocytosis, neurotoxin secretion, and cytokine secretion. Delivery of FK506 and tat-VIVIT to transgenic APP/PS1 mice attenuated spleen but not brain cytokine levels. However, FK506 and tat-VIVIT significantly attenuated both microgliosis and Aβ plaque load in treated mice compared to controls. Surprisingly, this did not correlate with changes in memory performance via T-maze testing.
  
  
  CONCLUSIONS
  Our findings suggest that development of specific NFAT inhibitors may offer promise as an effective strategy for attenuating the microgliosis and Aβ plaque deposition that occur in AD.
authors.affiliation: Institute of Science, Suranaree University of Technology, 111 University Avenue, Suranaree Subdistric, Nakhon Ratchasima, 30000, Thailand. lalida.rojanathammanee@gmail.com.|Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Neuroscience Building, Grand Forks, ND, 58203, USA. lalida.rojanathammanee@gmail.com.
authors.forename: Lalida
authors.initials: L
authors.lastname: Rojanathammanee
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Neuroscience Building, Grand Forks, ND, 58203, USA. angela.floden@med.und.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Floden
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Neuroscience Building, Grand Forks, ND, 58203, USA. gunjan.dhawan@med.und.edu.
authors.forename: Gunjan D
authors.initials: GD
authors.lastname: Manocha
authors.affiliation: Department of Basic Sciences, University of North Dakota School of Medicine and Health Sciences, 504 Hamline Street, Neuroscience Building, Grand Forks, ND, 58203, USA. colin.combs@med.und.edu.
authors.forename: Colin K
authors.initials: CK
authors.lastname: Combs
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016559:Tacrolimus