Loss of Endothelial APOE4 Dysregulates Neural Function In Vivo.

IF 6 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Journal of the American Heart Association Pub Date : 2024-12-03 Epub Date: 2024-11-29 DOI:10.1161/JAHA.124.035080

Felecia M Marottoli, Deebika Balu, Eden Flores-Barrera, Emilce Artur de la Villarmois, Hui Zhang, Rohan Chaudhary, Ruju Talati, Kuei Y Tseng, Leon M Tai

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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.

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体内内皮细胞APOE4缺失导致神经功能失调。

背景：我们最近发现内皮细胞APOE3的缺失会破坏神经血管和突触功能。然而，在生理条件下，内皮细胞APOE4对神经功能是有害还是有保护作用尚不清楚。因此，本研究的目的是确定内皮细胞APOE4在体内调节脑功能中的作用。方法与结果：建立APOE4fl/fl/Cdh5(PAC)- creert2 +/-和APOE4fl/fl/Cdh5(PAC)- creert2 -/-（对照）小鼠。在≈4 ~ 5周龄时诱导内皮细胞APOE4表达下调。实验在9月龄时进行，通过生物化学、免疫组织化学、行为测试和电生理来评估神经血管和神经元的功能。内皮细胞APOE4敲低导致神经血管通透性升高，claudin-5血管覆盖率降低，痕量恐惧记忆消退受损，皮层突触活性兴奋-抑制平衡被破坏。结论：我们的数据支持内皮细胞APOE4在其他细胞表达APOE4时对脑功能具有保护作用的新概念。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of the American Heart Association CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

9.40

自引率

1.90%

发文量

1749

审稿时长

12 weeks

期刊介绍： As an Open Access journal, JAHA - Journal of the American Heart Association is rapidly and freely available, accelerating the translation of strong science into effective practice. JAHA is an authoritative, peer-reviewed Open Access journal focusing on cardiovascular and cerebrovascular disease. JAHA provides a global forum for basic and clinical research and timely reviews on cardiovascular disease and stroke. As an Open Access journal, its content is free on publication to read, download, and share, accelerating the translation of strong science into effective practice.