Abstract WP97: Neuroprotective Effect of Progranulin Against Focal Cerebral Ischemia via Inhibition of Proteolysis of TDP-43 by Caspase-3

Abstract

Introduction: We previously demonstrated that progranulin (PGRN), a glycoprotein growth factor, may be a novel therapeutic target that provides vascular protection and anti-neuroinflammation properties related in part to vascular endothelial growth factor and interleukin 10, respectively. We also found that PGRN could provide neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 (TDP-43), although its exact mechanism remains poorly understood. The purpose of this study is to determine the mechanism of neuroprotection by PGRN against ischemic neuronal injury. Methods: The middle cerebral artery of adult PGRN knock-out (KO) mice (C57BL/6 background) and wild-type (WT) mice was occluded for 90 minutes. Immunohistochemical analysis using an antibody against TDP-43 was performed to investigate the subcellular localization of TDP-43 after ischemia. We also performed Western blot analysis to investigate the expression levels of TDP-43 and activated caspase-3 using cerebral cortex tissues from a rat autologous thromboembolic model with delayed tissue plasminogen activator (tPA) treatment (4 hours after ischemia). Results: Twenty-four hours after reperfusion, neuronal cells showing cytoplasmic redistribution of TDP-43 were more frequently observed in PGRN KO mice than in WT mice (P<0.01). In a rat autologous thromboembolic model with delayed tPA treatment, the expression level of full-length of TDP-43 decreased 24 hours after ischemia via proteolytic degradation. However, intravenous administration of recombinant PGRN with delayed tPA treatment inhibited the decrease in the expression level of full-length TDP-43 as well as the increase in the expression level of activated caspase-3 compared with that of the control protein. Conclusion: This study demonstrated that PGRN might protect neuronal cells against focal cerebral ischemia via inhibition of proteolysis and abnormal cytoplasmic redistribution of TDP-43 by caspase-3.