Saito Mariko, Saito Mitsuo, Das Bhaskar C
Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg, Orangeburg, NY, 10962, USA.
Department of Psychiatry, New York University Langone Medical Center, 550 First Avenue, New York, NY, 10016, USA.
Int J Dev Neurosci. 2019 Oct;77:48-59. doi: 10.1016/j.ijdevneu.2019.01.007. Epub 2019 Jan 29.
Microglial activation followed by neuroinflammation is a defense mechanism of the brain to eliminate harmful endogenous and exogenous materials including pathogens and damaged tissues, while excessive or chronic neuroinflammation may cause or exacerbate neurodegeneration observed in brain injuries and neurodegenerative diseases. Depending on conditions/environments during activation, microglia acquire distinct phenotypes, such as pro-inflammatory, anti-inflammatory, and disease-associated phenotypes, and show their ability to phagocytose various objects and produce pro-and anti-inflammatory mediators. Prevention of excessive inflammation by regulating the microglia's pro/anti-inflammatory balance is important for alleviating progression of brain injuries and diseases. Among many factors involved in the regulation of microglial phenotypes, cellular energy status plays an important role. Adenosine monophosphate-activated protein kinase (AMPK), which serves as a master sensor and regulator of energy balance, is considered a candidate molecule. Accumulating evidence from adult rodent studies indicates that AMPK activation promotes anti-inflammatory responses in microglia exposed to danger signals or various stressors mainly through inhibition of the nuclear factor κB (NF-κB) signaling and activation of the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway. However, AMPK activation in neurons exposed to stressors/insults may exacerbate neuronal damage if AMPK activation is excessive or prolonged. While AMPK affects microglial activation states and neuronal cell survival rates in both the adult and the developing brain, studies in the developing brain are still scarce, even though activated AMPK is highly expressed especially in the neonatal brain. More in depth studies in the developing brain are important, because neuroinflammation/neurodegeneration occurred during development can result in long-lasting brain damage.
小胶质细胞激活后引发神经炎症，这是大脑的一种防御机制，用于清除包括病原体和受损组织在内的有害内源性和外源性物质，而过度或慢性神经炎症可能导致或加剧在脑损伤和神经退行性疾病中观察到的神经退行性变。根据激活过程中的条件/环境，小胶质细胞会获得不同的表型，如促炎、抗炎和疾病相关表型，并展现出吞噬各种物体以及产生促炎和抗炎介质的能力。通过调节小胶质细胞的促炎/抗炎平衡来预防过度炎症，对于减轻脑损伤和疾病的进展至关重要。在调节小胶质细胞表型的众多因素中，细胞能量状态起着重要作用。作为能量平衡的主要传感器和调节因子的腺苷单磷酸激活蛋白激酶（AMPK）被认为是一个候选分子。来自成年啮齿动物研究的越来越多的证据表明，AMPK激活主要通过抑制核因子κB（NF-κB）信号传导和激活核因子红细胞2相关因子2（Nrf2）途径，促进暴露于危险信号或各种应激源的小胶质细胞中的抗炎反应。然而，如果AMPK激活过度或持续时间过长，暴露于应激源/损伤的神经元中的AMPK激活可能会加剧神经元损伤。虽然AMPK在成年和发育中的大脑中都会影响小胶质细胞的激活状态和神经元细胞存活率，但尽管激活的AMPK在新生儿脑中尤其高表达，关于发育中大脑的研究仍然很少。对发育中大脑进行更深入的研究很重要，因为发育过程中发生的神经炎症/神经退行性变可能会导致持久的脑损伤。
