The role of AMPK in psychosine mediated effects on oligodendrocytes and astrocytes: Implication for Krabbe Disease
The role of AMPK in psychosine mediated effects on oligodendrocytes and astrocytes: Implication for Krabbe Disease
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DOI：
10.1111/j.1471-4159.2008.05279.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Singh, Avtar K.
中科院分区：
文献类型：
--
作者：
Giri, Shailendra;Khan, Mushfiquddin;Singh, Avtar K.
克拉伯病（Krabbe disease， KD）是一种遗传性神经系统疾病，由半乳糖脑苷酶活性缺乏导致精神苷积累，导致能量消耗、少突胶质细胞损失、胶质细胞增生和中枢神经系统星形胶质细胞炎症引起。在这项研究中，我们首次报道了精神肽在少突胶质细胞和星形胶质细胞中调节“细胞能量开关”，即amp激活的蛋白激酶（AMPK）。精神素治疗显著下调AMPK活性，导致少突胶质细胞细胞系（MO3.13）和初代星形胶质细胞中胆固醇和游离脂肪酸等脂类生物合成增加。AMPK的药理激活剂，5-氨基咪唑-4-羧酰胺-1- β -4-核呋喃苷（AICAR）减弱了精神素介导的AMPK下调，恢复了被改变的脂质生物合成。AICAR治疗还可下调精神素诱导的原代星形胶质细胞中促炎细胞因子和诱导型一氧化氮合酶的表达。然而，AICAR治疗对精神素-活性氧的产生、花生四烯酸的释放和少突胶质细胞的死亡没有影响；这表明AMPK在星形胶质细胞中调节精神素介导的炎症反应，而不是在少突胶质细胞的细胞死亡中起特殊作用。本研究揭示了AMPK在精神素诱导的星形胶质细胞炎症中的明确作用，而不直接影响少突胶质细胞的细胞死亡。该研究还表明，AMPK激活剂可以作为抗炎剂，在克拉布病/痉挛病中具有治疗潜力，特别是当与保护少突胶质细胞细胞损失的药物（如sPLA2抑制剂）联合使用时
Krabbe disease (KD) is an inherited neurological disorder caused by the deficiency of galactocerebrosidase activity resulting in accumulation of psychosine, which leads to energy depletion, loss of oligodendrocytes, induction of gliosis, and inflammation by astrocytes in CNS. In this study, for the first time, we report the regulation of 'cellular energy switch,'AMP-activated protein kinase (AMPK), by psychosine in oligodendrocytes and astrocytes. Psychosine treatment significantly down-regulated AMPK activity, resulting in increased biosynthesis of lipids including cholesterol and free fatty acid in oligodendrocytes cell line (MO3.13) and primary astrocytes. Pharmacological activator of AMPK, 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuated the psychosine-mediated down-regulation of AMPK and restored altered biosynthesis of lipids. AICAR treatment also down-regulated psychosine induced expression of proinflammatory cytokines and inducible nitric oxide synthase in primary astrocytes. However, AICAR treatment had no effect on psychosine incluced-reactive oxygen species generation, arachidonic acid release, and death of oligodendrocytes; suggesting the specific role of AMPK in regulation of psychosine-mediated inflammatory response of astrocytes but not in cell death of oligodendrocytes. This study delineates an explicit role for AMPK in psychosine induced inflammation in astrocytes without directly affecting the cell death of oligodendrocytes. It also suggests that AMPK activating agents act as anti-inflammatory agents and can hold a therapeutic potential in Krabbe disease/twitcher disease, particularly when used in combination with drugs, which protect oligodendrocyte cell loss, such as sPLA2 inhibitor