Chang Ji Young, Kim Jiwon, Kim Jong Youl, Lee Jong Eun
Department of Anatomy, Yonsei University College of Medicine, Seoul 03722, Korea.
Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea.
Exp Neurobiol. 2025 Jun 30;34(3):95-107. doi: 10.5607/en25007.
Changes in microglia, a specialized population of glial cells found in the central nervous system (CNS), is often associated with hyperglycemic conditions. It has been reported that exogenous administration of agmatine (agm) has neuroprotective effects in CNS injuries, including neurodegenerative diseases, while also being involved with modulating macrophage subdivision. In this study, the effects of agmatine on microglial polarization has been investigated and whether this effect can be related to the modulation of autophagy in neuroinflammatory conditions induced by high glucose (HG) concentrations. Neuroinflammatory conditions were mimicked through treatment to BV2 microglial cells. BV2 cells were mainly induced into proinflammatory M1 phenotype when treated with HG (100 mM), shown by the increase in M1 marker, CD86, and shifted to M2 phenotype in HG condition with agm (100 μM), indicated by the upregulation of mannose receptor CD206. When agm was treated with HG, the level of LC3-II was increased while p62/SQSTM1 level was downregulated, and the expression of LAMP1 was increased. In transmission electron microscopy, autophagosomes has shown that HG conditions led to severe mitochondrial damage while elongating phagophore membranes and autolysosomes were seen in cells treated with HG and agm, showing stimulated mitophagy. In a high-fat diet-induced T2DM metabolic dementia animal model, agmatine administration upregulated autophagy and shifted microglial polarization from proinflammatory to anti-inflammatory phenotype, improving cognitive function and alleviating neuroinflammation. In this study, it has been demonstrated that agm treatment can ameliorate neuroinflammation by upregulating autophagy on a cellular level and shifting microglia polarization from M1 to M2 phenotype, showing a therapeutic potential in metabolic AD.
小胶质细胞是中枢神经系统（CNS）中一种特殊的神经胶质细胞群体，其变化通常与高血糖状况有关。据报道，外源性给予胍丁胺（agm）对中枢神经系统损伤具有神经保护作用，包括神经退行性疾病，同时还参与调节巨噬细胞亚群。在本研究中，研究了胍丁胺对小胶质细胞极化的影响，以及这种作用是否与高糖（HG）浓度诱导的神经炎症条件下自噬的调节有关。通过对BV2小胶质细胞进行处理来模拟神经炎症条件。当用HG（100 mM）处理时，BV2细胞主要被诱导为促炎M1表型，表现为M1标志物CD86增加；而在含有agm（100 μM）的HG条件下，细胞转变为M2表型，表现为甘露糖受体CD206上调。当用agm与HG共同处理时，LC3-II水平升高，而p62/SQSTM1水平下调，且LAMP1表达增加。在透射电子显微镜下，自噬体显示HG条件导致严重的线粒体损伤，而在用HG和agm处理的细胞中可见吞噬泡膜延长和自溶酶体，表明有刺激的线粒体自噬。在高脂饮食诱导的2型糖尿病代谢性痴呆动物模型中，给予胍丁胺可上调自噬，并使小胶质细胞极化从促炎表型转变为抗炎表型，改善认知功能并减轻神经炎症。在本研究中，已证明agm处理可通过在细胞水平上上调自噬并使小胶质细胞极化从M1表型转变为M2表型来改善神经炎症，显示出在代谢性阿尔茨海默病中的治疗潜力。
