title: Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.
abstract: OBJECTIVE
  Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD.
  
  
  METHODS
  The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting.
  
  
  RESULTS
  AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity.
  
  
  CONCLUSIONS
  Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Santiago V
authors.initials: SV
authors.lastname: Salazar
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Haas
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Jeng
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Robinson
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.|Department of Neurology, Yale University School of Medicine, New Haven, CT.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Gunther
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: van Dyck
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.|Department of Neurology, Yale University School of Medicine, New Haven, CT.
authors.forename: Haakon B
authors.initials: HB
authors.lastname: Nygaard
authors.affiliation: Department of Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT.|Department of Neurology, Yale University School of Medicine, New Haven, CT.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D052117:Benzodioxoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D051418:Focal Adhesion Kinase 2 / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C515233:saracatinib; D051418:Focal Adhesion Kinase 2; D051076:Proto-Oncogene Proteins c-fyn; C496053:Ptk2b protein, mouse