OBJECTIVE The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. CONCLUSIONS ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.

中文翻译：

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脑周细胞中的 ApoE（载脂蛋白 E）通过调节基底膜成分以异构体依赖性方式调节内皮功能。

目的与常见的ε3等位基因相比，APOE基因的ε4等位基因（APOE4）是阿尔茨海默病最强的遗传危险因素。尽管在了解 apoE4（载脂蛋白 E4）如何驱动淀粉样蛋白病理方面取得了重大进展，但其对淀粉样蛋白非依赖性途径的影响，特别是脑血管完整性和功能，尚不清楚。方法和结果：在这里，我们表明脑周细胞（毛细血管壁的壁细胞）以 apoE 异构体依赖性方式差异调节内皮细胞表型。与来自 apoE3-TR 小鼠的相比，与来自 apoE4 靶向替代 (TR) 小鼠的周细胞共培养的内皮细胞的细胞外基质蛋白诱导、管状结构形成和屏障形成较低。重要的，与 apoE3-TR 小鼠相比，老年 apoE4 靶向替代小鼠的细胞外基质蛋白表达降低，血浆蛋白渗漏增加。结论 ApoE4 会损害周细胞介导的基底膜形成，这可能有助于 apoE4 对脑血管的影响。