Abstract WP345: Syndecan-4 Is a Novel Target for Protecting Brain Against Ischemic Stroke

Introduction: Ischemic stroke is an acute metabolic and cerebrovascular disease that leads to high mortality and disability rate in the world. Database analysis in patients and rodents suggest Syndecan-4 (Sdc4) may play a potential role in ischemic stroke, but the underlying mechanisms remain unclear. As a kind of transmembrane core protein, Sdc4 may initiate intracellular signaling via either its protein core ectodomain or cytoplasmic domain. Therefore, it is of great significance to investigate the specific function of Sdc4 and its potential as a novel therapeutic target in ischemic stroke. Methods: The serum level of shed Sdc4 extracellular domain in patients with ischemic stroke and mice with transient middle cerebral artery occlusion (MCAO) was determined. Sdc4 global knockout mice (GKO) and their wildtype (WT) littermates were generated and subjected to MCAO to investigate whether Sdc4 deficiency alters functional outcome following ischemic stroke and its underlying mechanisms. Infarct volume, neurological deficits, neuroinflammation, and blood-brain barrier (BBB) integrity were assessed. Results: Shed Sdc4 level in the serum of both patients with ischemic stroke and mice with MCAO was decreased acutely at 24 hours after disease onset, while cerebral Sdc4 expression was significantly increased in the ipsilateral brain hemisphere of mice. Infiltrated macrophages were identified as the major cerebral source of Sdc4. Sdc4 deficiency reduced the infarct volume in mice subjected to MCAO, compared to that of the WT controls. Neurological deficit and neuroinflammation were also attenuated in Sdc4 GKO mice following MCAO. Furthermore, Sdc4 GKO mice showed an improved BBB integrity. Conclusions: These results reveal that altered serum and cerebral Sdc4 level are implicated in the pathogenesis of ischemic stroke. Genetic deletion of Sdc4 significantly prevents brain injury in mice at 24 hours following MCAO. Further investigation is warranted to explore underlying mechanisms of Sdc4 mediated brain injury in ischemic stroke.