Inserm UMR-S 942, Paris, France.
Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Alzheimers Dis. 2018;63(2):665-674. doi: 10.3233/JAD-171099.
Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n = 6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.
阿尔茨海默病（AD）的特征是淀粉样β（Aβ42）和过度磷酸化的tau 蛋白的积累，与神经炎症、突触丧失和神经元死亡有关。几项研究表明，c-Jun N 末端激酶（JNK）与 AD 的病理特征有关。我们在 5XFAD 小鼠中研究了 Brimapitide 的治疗效果，Brimapitide 是一种 JNK 特异性抑制肽，之前在另一种 AD 模型（TgCRND8）中用较高浓度进行了测试。3 个月大的 5XFAD 和野生型同窝小鼠通过静脉注射低剂量（10mg/kg）Brimapitide 每 3 周一次，持续 3 或 6 个月（每组 n=6-9）。使用 Y 迷宫、恐惧条件测试以及组织学和生化方法评估认知缺陷和脑部病变。Brimapitide 慢性治疗 3 个月可减少 5XFAD 治疗小鼠皮质中的 Aβ 斑块负担。治疗 6 个月后，认知缺陷减少，但也检测到治疗小鼠的细胞死亡标志物和促炎细胞因子 IL-1β 显著减少。6 个月的治疗不再改变 Aβ 斑块负担。除了调节认知和淀粉样斑块积累外，Brimapitide 似乎还根据治疗持续时间在实验中减轻 5XFAD 小鼠的神经元应激。
