Department of Neurology and Rehabilitation, The University of Illinois at Chicago, Chicago, Illinois 60612.
Department of Neurology and Rehabilitation, The University of Illinois at Chicago, Chicago, Illinois 60612
eNeuro. 2023 Nov 10;10(11). doi: 10.1523/ENEURO.0422-23.2023. Print 2023 Nov.
Plaque formation, microglial activation, and synaptic loss are pathologic hallmarks of Alzheimer's disease; however, removing plaques has had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity and augments microglial activation and plaque formation in 5XFAD Alzheimer's mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist, GlyB4, significantly alters microglial morphology and function to a nonpathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel "upstream" approach to slow or stop disease progression in Alzheimer's disease.
斑块形成、小胶质细胞激活和突触损失是阿尔茨海默病的病理标志；然而，清除斑块对临床治疗几乎没有益处。在这里，我们发现神经调节蛋白 1（一种神经胶质生长因子）可诱导炎症细胞因子的产生，并促进吞噬作用，从而增强 5XFAD 阿尔茨海默病小鼠的小胶质细胞激活和斑块形成。通过脑室给予新型神经调节蛋白 1 融合蛋白拮抗剂 GlyB4 对大脑中的神经调节蛋白 1 进行特异性靶向，可显著改变早期 5XFAD 小鼠小胶质细胞的形态和功能，使其向非致病性形态转变，并防止斑块形成。一旦斑块已经形成，GlyB4 可减少新斑块的形成并防止突触损失。用 GlyB4 选择性、靶向破坏大脑小胶质细胞上的神经调节蛋白 1 信号可能是一种新的“上游”方法，可减缓或阻止阿尔茨海默病的疾病进展。
