The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer’s disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.

载脂蛋白 E 基因 ( APOE4 ) 的 ε4 等位基因是阿尔茨海默病 (AD) 和多种血管疾病的强烈遗传风险因素。 ApoE 在多种脑细胞类型中大量表达，包括星形胶质细胞、小胶质细胞和血管壁细胞 (VMC)。在这里，我们发现 VMC 特异性表达 apoE4 会损害小鼠的行为和脑血管功能。 VMC 中 apoE3 或 apoE4 的表达足以挽救Apoe基因敲除小鼠中出现的高胆固醇血症和动脉粥样硬化表型。有趣的是，apoE4（而不是apoE3）的血管表达减少了小动脉血流量，损害了空间学习，并增加了焦虑样表型。血管和神经胶质细胞的单细胞 RNA 测序表明，VMC 中的 apoE4 与星形胶质细胞活化相关，而 apoE3 与周细胞中的血管生成特征相关。总之，我们的数据支持血管 apoE 以异构体依赖性方式对脑稳态的细胞自主影响，表明血管 apoE 对 AD 发病机制的关键贡献。