Gladen-Kolarsky Noah, Neff Cody J, Hack Wyatt, Brandes Mikah S, Wiedrick Jack, Meza-Romero Roberto, Lockwood Denesa R, Quinn Joseph F, Offner Halina, Vandenbark Arthur A, Gray Nora E
Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Biostatistics & Design Program, OHSU-PSU School of Public Health, Portland, OR, 97201, USA.
Metab Brain Dis. 2025 Jan 14;40(1):95. doi: 10.1007/s11011-024-01433-5.
Neuroinflammation and mitochondrial dysfunction are early events in Alzheimer's disease (AD) and contribute to neurodegeneration and cognitive impairment. Evidence suggests that the inflammatory axis mediated by macrophage migration inhibitory factor (MIF) binding to its receptor, CD74, plays an important role in many central nervous system (CNS) disorders such as AD. Our group has developed DRhQ, a novel CD74 binding construct which competitively inhibits MIF binding, blocks macrophage activation and migration into the CNS, enhances anti-inflammatory microglia cell numbers and reduces pro-inflammatory gene expression. Here, we evaluate its effects in amyloid-β (Aβ) overexpressing mice. 5xFAD mice and their wild type littermates were treated with DRhQ (100 µg) or vehicle for 4 weeks. DRhQ improved cognition and cortical mitochondrial function in both male and female 5xFAD mice. Aβ plaque burden in 5xFAD animals was not robustly impacted by DRhQ treatment in either the hippocampus or the cortex. Cortical microglial activation was similarly not apparently affected by DRhQ treatment, although in the hippocampus there was evidence of a reduction in activated microglia for female 5xFAD mice. Future studies are needed to confirm this possible sex-dependent response on microglial activation, as well as to optimize the dose and timing of DRhQ treatment and gain a better understanding of its mechanism of action in AD.
神经炎症和线粒体功能障碍是阿尔茨海默病（AD）的早期事件，并导致神经退行性变和认知障碍。有证据表明，由巨噬细胞迁移抑制因子（MIF）与其受体CD74结合介导的炎症轴在包括AD在内的许多中枢神经系统（CNS）疾病中起重要作用。我们团队开发了DRhQ，一种新型的CD74结合构建体，它能竞争性抑制MIF结合，阻止巨噬细胞激活并迁移至CNS，增加抗炎性小胶质细胞数量并降低促炎基因表达。在此，我们评估其在淀粉样β蛋白（Aβ）过表达小鼠中的作用。将5xFAD小鼠及其野生型同窝小鼠用DRhQ（100μg）或溶剂处理4周。DRhQ改善了雄性和雌性5xFAD小鼠的认知和皮质线粒体功能。DRhQ处理对5xFAD动物海马体或皮质中的Aβ斑块负荷没有显著影响。DRhQ处理同样未明显影响皮质小胶质细胞激活，尽管在海马体中，有证据表明雌性5xFAD小鼠的活化小胶质细胞减少。未来需要开展研究来证实这种小胶质细胞激活可能存在的性别依赖性反应，以及优化DRhQ治疗的剂量和时间，并更好地了解其在AD中的作用机制。
