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The Role of Agmatine in Modulating Autophagy Under Neuroinflammatory Conditions Induced by Metabolic Alteration in
Ji Young Chang1,2, Jiwon Kim1,2, Jong Youl Kim1,2
1Department of Anatomy, Yonsei University College of Medicine, Seoul 03722, Korea.
Abstract:
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.
Insights
Agmatine (agm) shifts microglia from a pro-inflammatory M1 to an anti-inflammatory M2 state by enhancing autophagy. This neuroprotective effect shows potential for treating metabolic dementia and Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial activation is linked to hyperglycemia and neuroinflammation.
- Agmatine (agm) exhibits neuroprotective properties and modulates immune cells.
- Autophagy plays a role in regulating microglial function.
Purpose of the Study:
- To investigate agmatine's effect on microglial polarization under high glucose conditions.
- To determine if agmatine-induced changes in microglia are mediated by autophagy modulation.
- To assess agmatine's therapeutic potential in a metabolic dementia model.
Main Methods:
- BV2 microglial cells treated with high glucose (HG) and agmatine (agm).
- Analysis of microglial M1/M2 markers (CD86, CD206).
- Assessment of autophagy markers (LC3-II, p62/SQSTM1, LAMP1) and autophagosome formation via transmission electron microscopy.
- In vivo study using a high-fat diet-induced T2DM metabolic dementia animal model.
Main Results:
- High glucose (HG) induced a proinflammatory M1 microglial phenotype (increased CD86).
- Agmatine (agm) treatment shifted microglia to an anti-inflammatory M2 phenotype (upregulated CD206) in HG conditions.
- Agmatine upregulated autophagy markers (LC3-II, LAMP1) and downregulated p62/SQSTM1, indicating stimulated mitophagy.
- Agmatine administration improved cognitive function and reduced neuroinflammation in the animal model.
Conclusions:
- Agmatine ameliorates neuroinflammation by upregulating autophagy and promoting M1 to M2 microglial polarization.
- Agmatine demonstrates therapeutic potential for neurodegenerative conditions associated with metabolic dysfunction, such as metabolic dementia and Alzheimer's disease.
