Sompol Pradoldej, Norris Christopher M
Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, United States.
Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
Front Aging Neurosci. 2018 Jul 9;10:199. doi: 10.3389/fnagi.2018.00199. eCollection 2018.
Mounting evidence supports a fundamental role for Ca dysregulation in astrocyte activation. Though the activated astrocyte phenotype is complex, cell-type targeting approaches have revealed a number of detrimental roles of activated astrocytes involving neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation. Work from our lab and others has suggested that the Ca/calmodulin dependent protein phosphatase, calcineurin (CN), provides a critical link between Ca dysregulation and the activated astrocyte phenotype. A proteolyzed, hyperactivated form of CN appears at high levels in activated astrocytes in both human tissue and rodent tissue around regions of amyloid and vascular pathology. Similar upregulation of the CN-dependent transcription factor nuclear factor of activated T cells (NFAT4) also appears in activated astrocytes in mouse models of Alzheimer's disease (ADs) and traumatic brain injury (TBI). Major consequences of hyperactivated CN/NFAT4 signaling in astrocytes are neuroinflammation, synapse dysfunction and glutamate dysregulation/excitotoxicity, which will be covered in this review article.
越来越多的证据支持钙调节异常在星形胶质细胞激活中起重要作用。尽管激活的星形胶质细胞表型复杂，但细胞类型靶向方法已揭示激活的星形胶质细胞的许多有害作用，包括神经炎症、突触毒性因子释放和谷氨酸调节丧失。我们实验室和其他实验室的研究表明，钙/钙调蛋白依赖性蛋白磷酸酶钙调神经磷酸酶（CN）在钙调节异常和激活的星形胶质细胞表型之间提供了关键联系。在人类组织和啮齿动物组织中，淀粉样蛋白和血管病变区域周围的激活星形胶质细胞中，一种蛋白水解的、高度活化形式的CN大量出现。在阿尔茨海默病（AD）和创伤性脑损伤（TBI）小鼠模型的激活星形胶质细胞中，也出现了类似的CN依赖性转录因子活化T细胞核因子（NFAT4）上调。星形胶质细胞中CN/NFAT4信号过度激活的主要后果是神经炎症、突触功能障碍和谷氨酸调节异常/兴奋性毒性，本文将对此进行阐述。
