Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function

Abstract

BACKGROUND: Specialized brain endothelial cells and human APOE3 are independently important for neurovascular function, yet whether APOE3 expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell APOE3 impacts brain vascular and neural function. METHODS: We developed APOE3 fl/fl /Cdh5(PAC)-CreERT2 +/− ( APOE3 Cre+/− ) and APOE3 fl/fl /Cdh5(PAC)-CreERT2 −/− ( APOE3 Cre −/− , control) mice and induced endothelial cell APOE3 knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age. RESULTS: We found that the loss of endothelial APOE3 expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance. CONCLUSIONS: Our data collectively support the novel concept that endothelial APOE3 plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.

The Influences of ApoE Isoforms on Endothelial Adherens Junctions and Actin Cytoskeleton Responding to mCRP

“…ApoE3 has been shown to inhibit Rho activation, reducing the formation of actin stress bers and focal adhesions and leading to cellular softening 46 . Speci c knock-out ApoE3 gene in endothelia causes neurovascular dysfunction and increase permeability in the mice 47 . Using ApoE-/mice, it has been demonstrated that the main proteins modulated by hyperlipidemic stress are involved in actin-dependent pathways 48 .…”