Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice

BMC Neuroscience

Luciana Giardino⁶  Laura Calzà⁶  Bruno P Imbimbo⁵  Gino Villetti⁵  Simone Ottonello¹  Arturo R Viscomi²  Maria Francesca Baroc⁴  Vladimiro Pietrini⁴  Luca Ferraro⁷  Chiara Mangano³  Vito Antonio Baldassarro³  Mercedes Fernandez³  Marco Gusciglio⁶  Alessandro Giuliani⁸  Luca Lorenzini⁸  Sandra Sivilia⁸ 

[1] Department of Biosciences, Biochemistry and Molecular Biology Unit, Laboratory of Functional Genomics and Protein Engineering, University of Parma, Parma, Italy;Present address: Microbiological Laboratory, GlaxoSmithKline Manufacturing Spa, Via Asolana 90, Parma, S.Polo di Torrile 43056, Italy;Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 50, Bologna, Ozzano Emilia I-40064, Italy;Department of Neurosciences, Laboratory of Neuropathology, University of Parma, Via Gramsci 14, Parma 43100, Italy;Research & Development, Chiesi Farmaceutici, Via Palermo 26/A, Parma 43100, Italy;IRET Foundation, Via Tolara di Sopra 50, Bologna, Ozzano Emilia 40064, Italy;Department of Life Sciences and biotechnology, University of Ferrara, Via Fossato di Mortara 17–19, Ferrara, Italy;Department of Veterinary Medicine, University of Bologna, Bologna, Italy

关键词: Tg2576 mice;    Dendrite pathology;    CHF5074;    Cell-cycle events;    Alzheimer’s disease;   

Others  :  1140343
DOI  :  10.1186/1471-2202-14-44

 received in 2012-09-10, accepted in 2013-03-14,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Sivilia et al.; licensee BioMed Central Ltd.

【 图 表 】

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