title: CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease.
abstract: OBJECTIVE
  We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).
  
  
  METHODS
  Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.
  
  
  RESULTS
  Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not beta-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.
  
  
  CONCLUSIONS
  Chronic CHF5074 treatment reduced brain beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease.
authors.affiliation: Research and Development, Chiesi Farmaceutici, Via Palermo, Parma, Italy. b.imbimbo@chiesigroup.com
authors.forename: B P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: B
authors.initials: B
authors.lastname: Hutter-Paier
authors.forename: G
authors.initials: G
authors.lastname: Villetti
authors.forename: F
authors.initials: F
authors.lastname: Facchinetti
authors.forename: V
authors.initials: V
authors.lastname: Cenacchi
authors.forename: R
authors.initials: R
authors.lastname: Volta
authors.forename: A
authors.initials: A
authors.lastname: Lanzillotta
authors.forename: M
authors.initials: M
authors.lastname: Pizzi
authors.forename: M
authors.initials: M
authors.lastname: Windisch
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D007859:Learning Disabilities / Q000188:drug therapy*; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000473:pathology
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003521:Cyclopropanes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases; D007052:Ibuprofen