期刊
GLIA
卷 60, 期 4, 页码 526-540出版社
WILEY
DOI: 10.1002/glia.22284
关键词
microglial activation; neuroinflammation; Alzheimer's disease; ERK1; 2; JNK; p38; TNFa; NO
资金
- Ministerio de Educacion y Ciencia [SAF2005-00704, SAF2008-04515]
- Fundacio La MaratoTV3 [051110]
- PETRI-FEDER/Ministerio de Educacion y Ciencia [PET2006_0514]
- Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion [PI080421, PI07/0455]
- Ministerio de Ciencia e Innovacion
Inflammatory responses mediated by glial cells play a critical role in many pathological situations related to neurodegeneration such as Alzheimer's disease. Tissue plasminogen activator (tPA) is a serine protease which best-known function is fibrinolysis, but it is also involved in many other physiological and pathological events as microglial activation. Here, we found that tPA is required for A beta-mediated microglial inflammatory response and tumor necrosis factor-a release. We further investigated the molecular mechanism responsible for tPA-mediated microglial activation. We found that tPA induces a catalytic-independent rapid and sustained activation of extracellular signal-regulated kinase (ERK)1/2, Jun N-terminal kinase (JNK), Akt, and p38 signaling pathways. Inhibition of ERK1/2 and JNK resulted in a strong inhibition of microglial activation, whereas Akt inhibition led to increased inflammatory response, suggesting specific functions for each signaling pathway in the regulation of microglial activation. Furthermore, we demonstrated that AnnexinA2 and Galectin-1 receptors are involved in tPA signaling and inflammatory response in glial cells. This study provides new evidences supporting that tPA plays a cytokine-like role in glial activation by triggering receptor-mediated intracellular signaling circuits and opens new therapeutic strategies for the treatment of neurological disorders in which neuroinflammation plays a pathogenic role. (c) 2011 Wiley Periodicals, Inc.
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