Department of Veterinary Medicine, University of Bologna, Bologna, Italy.
BMC Neurosci. 2013 Apr 5;14:44. doi: 10.1186/1471-2202-14-44.
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).
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.
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.
阿尔茨海默病是一种多因素疾病，其特征是神经元网络的进行性恶化。病理学特征包括细胞外淀粉样斑块和细胞内神经原纤维缠结，但主要原因仅部分了解。因此，人们越来越有兴趣开发可能针对导致神经元退化的多种机制的药物。CHF5074 是一种非甾体抗炎衍生药物，已被证明在体外表现为γ-分泌酶调节剂，并在阿尔茨海默病（AD）转基因小鼠模型中抑制斑块沉积和逆转记忆缺陷。在本研究中，评估了长期（13 个月）用 CHF5074 治疗对转基因 AD 小鼠（Tg2576）脑功能和神经退行性变指标的影响，并与典型γ-分泌酶抑制剂（DAPT）的影响进行了比较。
为此，对无斑块的 6 月龄 Tg2576 小鼠和野生型同窝小鼠进行了喂养，饮食中含有 CHF5074（每天 125 和 375ppm），DAPT（每天 375ppm）或载体 13 个月。测量的指标包括物体识别记忆，淀粉样蛋白负荷，脑寡聚物和血浆 Aβ水平，细胞内 Aβ，树突棘密度/形态，神经元细胞周期蛋白 A 阳性和激活的小胶质细胞。用标准饮食喂养的 Tg2576 小鼠表现出识别记忆障碍。较高剂量的 CHF5074 完全逆转了这种缺陷，而 DAPT 治疗的小鼠则没有观察到这种作用。同样，CHF5074 处理显著影响淀粉样斑块负担，小胶质细胞激活和异常细胞周期事件，但 DAPT 处理没有影响。CHF5074 和 DAPT 均可降低细胞内 Aβ含量，同时增加 Aβ40 和 Aβ42 血浆水平。
这项比较分析揭示了一系列临床上相关的显著差异，这些差异将多功能抗炎衍生药物 CHF5074 与 γ-分泌酶抑制剂 DAPT 区分开来，并强调了可能对 AD 小鼠模型中的神经保护至关重要的独特机制和潜在靶标。
