KLKB1 Knockdown Alleviates Cognitive Disorder via Inhibiting Ferroptosis in Vascular Dementia

Abstract

Background: Ferroptosis is a new form of iron-dependent cell death associated with the pathophysiology of vascular dementia (VD). However, the specific mechanism of action is still unclear. This study aims to explore the specific mechanism of action between ferroptosis and VD to find effective therapeutic targets. Methods: Mice were treated with bilateral common carotid artery stenosis (BCAS) to mimic VD models. Neurological function was evaluated using a Morris water maze and mouse hippocampal pathology. Transcriptomic sequencing was performed on hippocampal tissue to search for target genes related to ferroptosis, which was validated in oxygen-glucose deprivation (OGD) treated PC12 cells. Iron content, reactive oxygen species (ROS), and lipid hydroperoxide (LPO) levels were measured. Glutathione peroxidase 4 (GPX4) and long-chain acyl-CoA synthetase 4 (ACSL4) levels were measured using WB (Western Blot) and qPCR (Quantitative Polymerase Chain Reaction), respectively. Results: Plasma prekallikrein (KLKB1, PK) levels were elevated in the hippocampal of BCAS-induced mice and OGD-exposed PC12 cells. Compared with the blank group, KLKB1 knockdown protected PC12 cells from OGD-induced apoptosis, and KLKB1 knockdown reduced ROS production and lipid peroxidation in PC12 cells. Besides, KLKB1 knockdown decreased iron content and elevated GPX4 expression. Conclusions: KLKB1 knockdown alleviates cognitive disorder via inhibiting ferroptosis in VD. Inhibition of oxidative stress, lipid peroxidation and reduction of iron content are involved in the underlying mechanisms.