The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2024-09-14 DOI:10.1007/s10456-024-09946-4

Zhengrong Zhang, Weiwei Lin, Qini Gan, Maohua Lei, Bin Gong, Chao Zhang, Jessica Salles Henrique, Jingyan Han, Hua Tian, Qiushan Tao, Lawrence A. Potempa, Thor D. Stein, Andrew Emili, Wei Qiao Qiu

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Abstract

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer’s disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk.

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载脂蛋白 E 同工酶对内皮粘连接头和肌动蛋白细胞骨架对 mCRP 反应的影响

载脂蛋白 E4（ApoE4）通过与 CD31 结合对单体 C 反应蛋白（mCRP）做出反应，从而导致脑血管损伤和阿尔茨海默病（AD）。通过磷酸蛋白组分析，我们发现 AD 大脑微血管中的细胞骨架蛋白发生了改变，包括高磷酸化 tau（pTau）和肌动蛋白相关蛋白 LIMA1 水平的升高。为了解决细胞骨架变化是载脂蛋白E4携带者脑内皮细胞中与CD31相关的早期病理特征这一假设，腹腔注射mCRP的载脂蛋白E4基因敲入小鼠发现，mCRP增加了磷酸化CD31（pCD31）和LIMA1的表达，并促进了pCD31与LIMA1的结合。mCRP 与重组 APOE4 蛋白结合后，CD31 与 VE-Cadherin 在粘连连接（AJ）处的相互作用减少，各种肌动蛋白细胞骨架蛋白的表达也发生改变，从而导致微血管损伤。值得注意的是，APOE2 蛋白可减轻这些变化。总之，我们的研究表明，载脂蛋白E4会对mCRP做出反应，从而破坏与肌动蛋白细胞骨架相联系的内皮AJ，这一途径可能在导致AD风险的屏障功能障碍中发挥关键作用。

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

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.