Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo

Abstract

Background We recently found that loss of endothelial cell APOE3 disrupts neurovascular and synaptic function. However, whether endothelial APOE4 is detrimental or protective for neural function under physiological conditions is unknown. Therefore, the goal of this study was to determine the role of endothelial cell APOE4 in regulating brain function in vivo. Methods and Results We developed APOE4 fl/fl /Cdh5(PAC)‐CreERT2 +/− and APOE4 fl/fl /Cdh5(PAC)‐CreERT2 −/− (control) mice. Knockdown of endothelial cell APOE4 was induced at ≈4 to 5 weeks of age. Experiments were conducted at 9 months of age to evaluate neurovascular and neuronal function via biochemistry, immunohistochemistry, behavior tests, and electrophysiology. Endothelial cell APOE4 knockdown resulted in higher neurovascular permeability, lower claudin‐5 vessel coverage, impaired trace fear memory extinction, and disruption of cortical excitatory‐inhibitory balance of synaptic activity. Conclusions Our data support the novel concept that endothelial cell APOE4 is protective for brain function when other cell types express APOE4 .