Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.
Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice.
复制标题
DOI：
10.3233/jad-190588
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Slusher BS
中科院分区：
文献类型：
--
作者：
Hollinger KR;Zhu X;Khoury ES;Thomas AG;Liaw K;Tallon C;Wu Y;Prchalova E;Kamiya A;Rojas C;Kannan S;Slusher BS
鉴于人口的老龄化，确定有效的治疗阿尔茨海默病（AD）是至关重要的。我们使用人源化APOE 4基因敲入小鼠模型研究了脑穿透性谷氨酰胺拮抗剂JHU-083治疗AD的疗效。使用BV 2细胞和从成年APOE 4敲入小鼠的海马分离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诱导的精氨酸酶（GLS）活性和炎性标志物的影响。通过经口管饲法向6月龄APOE 4敲入小鼠施用JHU-083或媒介物3次/周，持续4-5个月，并使用巴恩斯迷宫评估认知表现。使用放射性标记的GLS酶活性测定法确认脑中的靶标结合，并进行电生理学、胃肠道组织学、血液化学和CBC分析以评价JHU-083的耐受性。JHU-083抑制LPS介导的GLS活性增加，一氧化氮释放，以及培养的BV 2细胞和分离自APOE 4敲入AD小鼠的原代小胶质细胞中促炎细胞因子产生。在APOE 4小鼠中用JHU-083长期治疗改善了海马依赖性巴恩斯迷宫表现。与细胞培养结果一致，APOE 4小鼠的尸检分析显示，与年龄匹配的对照组相比，海马CD 11b+富集细胞中的GLS活性增加，这通过JHU-083治疗完全正常化。JHU-083耐受性良好，未显示出体重减轻效果或明显的行为变化。外周神经功能、胃肠道组织病理学和CBC/临床化学参数均不受慢性JHU-083治疗的影响。这些结果表明，JHU-083对上调的海马转氨酶的减弱代表了AD的新治疗策略。
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.