Afridi Ruqayya, Lee Won-Ha, Suk Kyoungho
Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, South Korea.
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea.
Front Cell Neurosci. 2020 Aug 13;14:246. doi: 10.3389/fncel.2020.00246. eCollection 2020.
Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review article, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.
在许多神经退行性疾病中都观察到与年龄相关的小胶质细胞慢性炎症激活及其功能障碍，最近已证实这些功能失调的细胞对神经退行性变的潜在影响。小胶质细胞的看家功能和防御功能，如监测脑实质和损伤后吞噬神经元碎片，对脑内环境稳定和免疫很重要。在神经退行性疾病期间，这些功能的丧失可通过产生促炎细胞因子和增加氧化应激来促进疾病病理过程，从而加剧持续的神经炎症。除了传统的M1/M2模式外，最近小胶质细胞研究的激增揭示了与衰老和神经退行性疾病相关的无数小胶质细胞表型。这些表型中的每一种都可以通过不同的转录谱以及改变的代谢、迁移和吞噬特性来表征。髓系细胞2（Trem2）和颗粒蛋白（GRN）上表达的触发受体突变与各种神经退行性疾病有关，并且这些基因在大多数最近确定的小胶质细胞表型中表达失调。这些基因主要通过代谢调节作为检查点调节因子并维持小胶质细胞的炎症适应性。功能失调的小胶质细胞通常表现出线粒体缺陷、糖酵解升高和脂滴积累，这导致迁移和吞噬减少以及促炎细胞因子分泌和活性氧释放增加。在这篇小型综述文章中，我们讨论了关于功能失调的小胶质细胞代谢紊乱及其与神经退行性变的记录关联的现有数据，强调了衰老诱导的慢性小胶质细胞激活如何改变小胶质细胞生物能量学，导致稳态和看家功能受损。功能失调的小胶质细胞引发或加剧神经退行性变，功能失调过程中涉及的关键途径，包括代谢，可能代表纠正失衡的潜在干预靶点。
