Yamamoto Masaya, Itokazu Takahide, Uno Hiroki, Maki Takakuni, Shibuya Nao, Yamashita Toshihide
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan; Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Neurotherapeutics. 2025 Mar;22(2):e00500. doi: 10.1016/j.neurot.2024.e00500. Epub 2024 Nov 29.
Repulsive Guidance Molecule A (RGMa) is well-recognized for its role in axon guidance. Recent studies have unveiled its diverse functions under pathological conditions within the central nervous system, such as spinal cord injury, multiple sclerosis, and Parkinson's disease. In this study, we explored the involvement of RGMa and the therapeutic effects of an anti-RGMa neutralizing antibody in a mouse model of vascular dementia (VaD). The VaD mouse model was established using the bilateral common carotid artery stenosis (BCAS) method. Immunohistochemical analysis revealed that these mice exhibited increased RGMa expression in the hippocampus, which coincided with reduced neurogenesis and impaired cholinergic innervation. These alterations manifested as cognitive impairments in the BCAS mice. Significantly, treatment with anti-RGMa neutralizing antibody reversed these pathological changes and cognitive deficits. Our findings suggest that RGMa plays a pivotal role in VaD pathology within the hippocampus and propose the anti-RGMa antibody as a promising therapeutic avenue for treating VaD.
排斥导向分子A（RGMa）因其在轴突导向中的作用而广为人知。最近的研究揭示了它在中枢神经系统病理条件下的多种功能，如脊髓损伤、多发性硬化症和帕金森病。在本研究中，我们探讨了RGMa在血管性痴呆（VaD）小鼠模型中的作用以及抗RGMa中和抗体的治疗效果。采用双侧颈总动脉狭窄（BCAS）法建立VaD小鼠模型。免疫组织化学分析显示，这些小鼠海马区RGMa表达增加，这与神经发生减少和胆碱能神经支配受损相吻合。这些改变在BCAS小鼠中表现为认知障碍。值得注意的是，用抗RGMa中和抗体治疗可逆转这些病理变化和认知缺陷。我们的研究结果表明，RGMa在海马区VaD病理中起关键作用，并提出抗RGMa抗体是治疗VaD的一种有前景的治疗途径。
