title: Chronic treatment with a novel γ-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease.
abstract: OBJECTIVE
  γ-Secretase modulators represent a promising therapeutic approach for Alzheimer's disease (AD) because they selectively decrease amyloid β 42 (Aβ42), a particularly neurotoxic Aβ species that accumulates in plaques in the brains of patients with AD. In the present study, we describe the in vitro and in vivo pharmacological properties of a potent novel γ-secretase modulator, 2-(S)-(3,5-bis(4-(trifluoromethyl)phenyl)phenyl)-4-methylpentanoic acid (JNJ-40418677).
  
  
  METHODS
  The potency and selectivity of JNJ-40418677 for Aβ reduction was investigated in human neuroblastoma cells, rat primary neurones and after treatment with single oral doses in non-transgenic mouse brains. To evaluate the effect of JNJ-40418677 on plaque formation, Tg2576 mice were treated from 6 until 13 months of age via the diet.
  
  
  RESULTS
  JNJ-40418677 selectively reduced Aβ42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain Aβ42 levels. Chronic treatment of Tg2576 mice with JNJ-40418677 reduced brain Aβ levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice.
  
  
  CONCLUSIONS
  JNJ-40418677 selectively decreased Aβ42 production, showed an excellent brain penetration after oral administration in mice and lowered brain Aβ burden in Tg2576 mice after chronic treatment. JNJ-40418677 therefore warrants further investigation as a potentially effective disease-modifying therapy for AD.
authors.affiliation: Neuroscience Department, Johnson & Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, Beerse, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Van Broeck
authors.forename: J-M
authors.initials: JM
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Tréton
authors.forename: M
authors.initials: M
authors.lastname: Desmidt
authors.forename: C
authors.initials: C
authors.lastname: Hopf
authors.forename: N
authors.initials: N
authors.lastname: Ramsden
authors.forename: E
authors.initials: E
authors.lastname: Karran
authors.forename: M
authors.initials: M
authors.lastname: Mercken
authors.forename: A
authors.initials: A
authors.lastname: Rowley
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: C562066:2-(3,5-bis(4-(trifluoromethyl)phenyl)phenyl)-4-methylpentanoic acid; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010421:Pentanoic Acids; D051880:Receptors, Notch; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D053829:Amyloid Precursor Protein Secretases