title: Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice.
abstract: BACKGROUND
  Alzheimer disease is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The pathological hallmarks includes extracellular amyloid plaques and intraneuronal neurofibrillary tangles, but the primary cause is only partially understood. Thus, there is growing interest in developing agents that might target multiple mechanisms leading to neuronal degeneration. CHF5074 is a nonsteroidal anti-inflammatory derivative that has been shown to behave as a γ-secretase modulator in vitro and to inhibit plaque deposition and to reverse memory deficit in vivo in transgenic mouse models of Alzheimer's disease (AD). In the present study, the effects of a long-term (13-month) treatment with CHF5074 on indicators of brain functionality and neurodegeneration in transgenic AD mice (Tg2576) have been assessed and compared with those induced by a prototypical γ-secretase inhibitor (DAPT).
  
  
  RESULTS
  To this end, plaque-free, 6-month-old Tg2576 mice and wild-type littermates were fed with a diet containing CHF5074 (125 and 375 ppm/day), DAPT (375 ppm/day) or vehicle for 13 months. The measured indicators included object recognition memory, amyloid burden, brain oligomeric and plasma Aβ levels, intraneuronal Aβ, dendritic spine density/morphology, neuronal cyclin A positivity and activated microglia. Tg2576 mice fed with standard diet displayed an impairment of recognition memory. This deficit was completely reverted by the higher dose of CHF5074, while no effects were observed in DAPT-treated mice. Similarly, amyloid plaque burden, microglia activation and aberrant cell cycle events were significantly affected by CHF5074, but not DAPT, treatment. Both CHF5074 and DAPT reduced intraneuronal Aβ content, also increasing Aβ40 and Aβ42 plasma levels.
  
  
  CONCLUSIONS
  This comparative analysis revealed a profoundly diverse range of clinically relevant effects differentiating the multifunctional anti-inflammatory derivative CHF5074 from the γ-secretase inhibitor DAPT and highlighted unique mechanisms and potential targets that may be crucial for neuroprotection in mouse models of AD.
authors.affiliation: Department of Veterinary Medicine, University of Bologna, Bologna, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sivilia
authors.forename: Luca
authors.initials: L
authors.lastname: Lorenzini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuliani
authors.forename: Marco
authors.initials: M
authors.lastname: Gusciglio
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernandez
authors.forename: Vito Antonio
authors.initials: VA
authors.lastname: Baldassarro
authors.forename: Chiara
authors.initials: C
authors.lastname: Mangano
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.forename: Vladimiro
authors.initials: V
authors.lastname: Pietrini
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Baroc
authors.forename: Arturo R
authors.initials: AR
authors.lastname: Viscomi
authors.forename: Simone
authors.initials: S
authors.lastname: Ottonello
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Laura
authors.initials: L
authors.lastname: Calzà
authors.forename: Luciana
authors.initials: L
authors.lastname: Giardino
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D019925:Cyclin A / Q000378:metabolism; D003521:Cyclopropanes / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D021641:Recognition, Psychology / Q000187:drug effects; D016622:Silver Staining
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; D014150:Antipsychotic Agents; D019925:Cyclin A; D003521:Cyclopropanes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005480:Flurbiprofen; D010751:Phosphopyruvate Hydratase
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