Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
Departments of Neurology, Johns Hopkins University, Baltimore, MD, USA.
J Alzheimers Dis. 2020;77(1):437-447. doi: 10.3233/JAD-190588.
Given the emergent aging population, the identification of effective treatments for Alzheimer's disease (AD) is critical.
We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model.
Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083.
JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings,postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment.
These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.
鉴于人口老龄化的出现，寻找有效的阿尔茨海默病（AD）治疗方法至关重要。
我们使用载脂蛋白 E4 敲入（APOE4KI）小鼠模型，研究了穿透血脑屏障的谷氨酸盐拮抗剂 JHU-083 治疗 AD 的疗效。
使用 BV2 细胞和源自 APOE4KI 小鼠海马的原代小胶质细胞进行细胞培养研究，以评估 JHU-083 处理对 LPS 诱导的谷氨酰胺酶（GLS）活性和炎症标志物的影响。6 月龄的 APOE4KI 小鼠经口灌胃给予 JHU-083 或载体，每周 3 次，持续 4-5 个月，并使用 Barnes 迷宫评估认知表现。使用放射性标记的 GLS 酶活性测定法确认脑内的靶标结合，进行电生理学、胃肠道组织学、血液化学和全血细胞计数分析，以评估 JHU-083 的耐受性。
JHU-083 抑制 LPS 介导的培养的 BV2 细胞和源自 APOE4KI AD 小鼠的原代小胶质细胞中 GLS 活性、一氧化氮释放和促炎细胞因子产生的增加。在 APOE4 小鼠中进行的 JHU-083 慢性治疗改善了海马依赖性 Barnes 迷宫表现。与细胞培养结果一致，APOE4 小鼠的死后分析显示，与年龄匹配的对照相比，海马 CD11b+富集细胞中的 GLS 活性增加，而 JHU-083 治疗完全使 GLS 活性正常化。JHU-083 具有良好的耐受性，没有体重减轻效应或明显的行为变化。慢性 JHU-083 治疗对周围神经功能、胃肠道组织病理学和全血细胞计数/临床化学参数均无影响。
这些结果表明，JHU-083 降低海马中上调的谷氨酰胺酶活性代表了 AD 的一种新的治疗策略。
