Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, De Boelelaan 1108, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Amsterdam, the Netherlands.
Cell Death Dis. 2023 Nov 28;14(11):781. doi: 10.1038/s41419-023-06316-8.
In Alzheimer's disease (AD) more than 50% of the patients are affected by capillary cerebral amyloid-angiopathy (capCAA), which is characterized by localized hypoxia, neuro-inflammation and loss of blood-brain barrier (BBB) function. Moreover, AD patients with or without capCAA display increased vessel number, indicating a reactivation of the angiogenic program. The molecular mechanism(s) responsible for BBB dysfunction and angiogenesis in capCAA is still unclear, preventing a full understanding of disease pathophysiology. The Liver X receptor (LXR) family, consisting of LXRα and LXRβ, was reported to inhibit angiogenesis and particularly LXRα was shown to secure BBB stability, suggesting a major role in vascular function. In this study, we unravel the regulatory mechanism exerted by LXRα to preserve BBB integrity in human brain endothelial cells (BECs) and investigate its role during pathological conditions. We report that LXRα ensures BECs identity via constitutive inhibition of the transcription factor SNAI2. Accordingly, deletion of brain endothelial LXRα is associated with impaired DLL4-NOTCH signalling, a critical signalling pathway involved in vessel sprouting. A similar response was observed when BECs were exposed to hypoxia, with concomitant LXRα decrease and SNAI2 increase. In support of our cell-based observations, we report a general increase in vascular SNAI2 in the occipital cortex of AD patients with and without capCAA. Importantly, SNAI2 strongly associated with vascular amyloid-beta deposition and angiopoietin-like 4, a marker for hypoxia. In hypoxic capCAA vessels, the expression of LXRα may decrease leading to an increased expression of SNAI2, and consequently BECs de-differentiation and sprouting. Our findings indicate that LXRα is essential for BECs identity, thereby securing BBB stability and preventing aberrant angiogenesis. These results uncover a novel molecular pathway essential for BBB identity and vascular homeostasis providing new insights on the vascular pathology affecting AD patients.
在阿尔茨海默病（AD）中，超过 50%的患者受到毛细血管脑淀粉样血管病（capCAA）的影响，其特征为局部缺氧、神经炎症和血脑屏障（BBB）功能丧失。此外，有或没有 capCAA 的 AD 患者显示血管数量增加，表明血管生成程序重新激活。导致 capCAA 中 BBB 功能障碍和血管生成的分子机制尚不清楚，这阻碍了对疾病病理生理学的全面理解。肝 X 受体（LXR）家族由 LXRα 和 LXRβ 组成，据报道其可抑制血管生成，特别是 LXRα 被证明可确保 BBB 的稳定性，这表明其在血管功能中起主要作用。在这项研究中，我们揭示了 LXRα 在人脑血管内皮细胞（BEC）中维持 BBB 完整性的调节机制，并研究了其在病理条件下的作用。我们报告 LXRα 通过组成性抑制转录因子 SNAI2 来确保 BEC 的身份。因此，大脑内皮细胞 LXRα 的缺失与 DLL4-NOTCH 信号的受损有关，这是一个涉及血管发芽的关键信号通路。当 BEC 暴露于缺氧时，也观察到类似的反应，同时 LXRα 减少和 SNAI2 增加。为了支持我们的细胞观察结果，我们报告 AD 患者和有或没有 capCAA 的患者的 occipital 皮质中血管 SNAI2 普遍增加。重要的是，SNAI2 与血管淀粉样蛋白-β沉积和血管生成素样 4 强烈相关，后者是缺氧的标志物。在缺氧的 capCAA 血管中，LXRα 的表达可能会减少，导致 SNAI2 的表达增加，从而导致 BEC 去分化和发芽。我们的研究结果表明，LXRα 对 BEC 身份至关重要，从而确保 BBB 的稳定性并防止异常血管生成。这些结果揭示了一个新的分子途径，对于 BBB 身份和血管稳态至关重要，为影响 AD 患者的血管病理学提供了新的见解。
