Tissue plasminogen activator induces microglial inflammation via a non-catalytic molecular mechanism involving activation of MAPKs and AKT signalling pathways and AnnexinA2 and Galectin1 receptors

Running Title: tPA-mediated glial activation signalling pathways. ABSTRACT 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 Aβ-mediated microglial inflammatory response and TNF 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 ERK1/2, JNK, AKT and p38 signalling 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 signalling pathway in the regulation of microglial activation. Furthermore, we demonstrated that AnnexinA2 and Galectin1 receptors are involved in tPA signalling and inflammatory response in glial cells. The present study provides new evidences supporting that tPA plays a cytokine-like role in glial activation by triggering receptor-mediated intracellular signalling circuits and opens new therapeutic strategies for the treatment of neurological disorders in which neuroinflammation plays a pathogenic role.