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.
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 transgenicmouse 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 transgenicADmice (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 Tg2576mice 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. Tg2576mice 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: M T Heneka; M P Kummer; S Weggen; B Bulic; G Multhaup; L Münter; M Hüll; T Pflanzner; C U Pietrzik Journal: Curr Alzheimer Res Date: 2011-03 Impact factor: 3.498
Authors: Ilse Dewachter; Delphine Reversé; Nathalie Caluwaerts; Laurence Ris; Cuno Kuipéri; Chris Van den Haute; Kurt Spittaels; Lieve Umans; Lutgarde Serneels; Els Thiry; Dieder Moechars; Mark Mercken; Emile Godaux; Fred Van Leuven Journal: J Neurosci Date: 2002-05-01 Impact factor: 6.167
Authors: Catherine R Burton; Jere E Meredith; Donna M Barten; Margi E Goldstein; Carol M Krause; Cathy J Kieras; Lisa Sisk; Lawrence G Iben; Craig Polson; Mark W Thompson; Xu-Alan Lin; Jason Corsa; Tracey Fiedler; Maria Pierdomenico; Yang Cao; Arthur H Roach; Joseph L Cantone; Michael J Ford; Dieter M Drexler; Richard E Olson; Michael G Yang; Carl P Bergstrom; Kate E McElhone; Joanne J Bronson; John E Macor; Yuval Blat; Robert H Grafstrom; Andrew M Stern; Dietmar A Seiffert; Robert Zaczek; Charles F Albright; Jeremy H Toyn Journal: J Biol Chem Date: 2008-06-23 Impact factor: 5.157
Authors: Gonzalo Acero; Miryam Nava Catorce; Ricardo González-Mendoza; Marco Antonio Meraz-Rodríguez; Luis Fernando Hernández-Zimbron; Roberto González-Salinas; Goar Gevorkian Journal: Inflammopharmacology Date: 2017-05-19 Impact factor: 4.473
Authors: Marissa J Schafer; Melissa J Alldred; Sang Han Lee; Michael E Calhoun; Eva Petkova; Paul M Mathews; Stephen D Ginsberg Journal: Neurobiol Aging Date: 2014-12-04 Impact factor: 4.673
Authors: Susan A Farr; Michelle A Erickson; Michael L Niehoff; William A Banks; John E Morley Journal: J Alzheimers Dis Date: 2014 Impact factor: 4.472
Authors: Salvatore Rinaldi; Laura Calzà; Luciana Giardino; Gabriele E M Biella; Antonio G Zippo; Vania Fontani Journal: Front Psychiatry Date: 2015-02-17 Impact factor: 4.157