Role of canonical Wnt pathway in regulating the structural and functional integrity of the blood-brain barrier in the normal adult brain

大脑功能在很大程度上依赖于通过密集的血管网络提供氧气和营养。脑血管由内皮细胞构成，内皮细胞是特化的血管细胞。大脑内皮细胞紧密地密封在一起，形成一个动态屏障，严格调节大脑和血液循环之间的交换，保护大脑免受血液循环中有毒物质的侵害。脑血管与其他大脑细胞密切互动，使大脑正常运作。在整个生命周期中，大脑稳定了脑血管的结构和功能完整性，以维持适合神经细胞功能和生存的最佳环境。尽管如此，维持成人正常大脑血管完整性的机制仍然是完全难以捉摸的。正常的衰老已被证明通过增加血管内皮屏障的渗透性来影响脑血管的功能。重要的是，我们的工作表明，典型的Wnt通路在维持成人大脑血管完整性方面起着关键作用。典型的Wnt通路是一种进化保守的细胞内机制，最近被证明在胚胎发育期间控制脑血管的形成和成熟。它在成人大脑中的作用是完全未知的。我们的数据表明，在正常衰老过程中，这一通路在脑血管内皮细胞中失活。我们的研究结果表明，该通路的基础活性是维持成人大脑血管完整性所必需的。此外，我们的数据显示，当载脂蛋白E （ApoE4）的E4变体存在时，该途径在脑血管内皮细胞中失活，ApoE4是一种参与脂质转运和加工的蛋白质。在人类中，ApoE存在三种变体，分别是E2、E3和E4。最近的报道表明，ApoE4变异与血管内皮屏障通透性增加有关。我们的研究结果表明，ApoE4受试者的脑血管完整性受损是由于典型的Wnt通路失活。本项目旨在剖析典型Wnt通路在正常成人大脑中对脑血管结构和功能完整性的调节作用，研究正常衰老过程中该通路的调节作用，并表征ApoE变异对脑血管典型Wnt通路的调节作用。该研究项目将通过对维持成人大脑血管完整性的机制提供新的见解，对脑血管生物学领域的大量知识的获取做出重大贡献。

Brain function narrowly depends upon the supply of oxygen and nutrients through the dense network of blood vessels. Cerebral blood vessels are constituted of endothelial cells, which are specialized vascular cells. Cerebral endothelial cells are tightly sealed together forming a dynamic barrier that strictly regulates the exchange between the brain and the blood circulation, and protects the brain from toxic substances present in the blood circulation. The cerebral blood vessels intimately interact with other brain's cells to enable the proper functioning of the brain. Throughout lifespan, the brain stabilizes the structural and functional integrity of the cerebral blood vessels in order to maintain an optimal environment suitable for the function and survival of nerve cells. Nonetheless, the mechanisms involved in maintaining the integrity of cerebral blood vessels in the adult normal brain remain totally elusive. Normal ageing has been shown to affect the function of cerebral blood vessels by increasing the permeability of the vascular endothelial barrier. Importantly, our work is suggesting that the canonical Wnt pathway plays a key role in maintaining the integrity of cerebral blood vessels in the adult brain. The canonical Wnt pathway is an evolutionary conserved intra-cellular mechanism that has been recently shown to control the formation and maturation of cerebral blood vessels during embryonic development. Its role in the adult brain is totally unknown. Our data indicate that the pathway is deactivated in cerebral vascular endothelial cells during normal ageing. Our results suggest that the basal activity of the pathway is required to maintain the integrity of cerebral blood vessels in the adult brain. Additionally, our data show that the pathway is deactivated in cerebral vascular endothelial cells in the presence of the E4 variant of apolipoprotein E (ApoE4), which is a protein involved in lipid transport and processing. In human, three variant of ApoE exists, the variants E2, E3 and E4. Recent reports have demonstrated that the ApoE4 variant is associated to an increased permeability of the vascular endothelial barrier. Our results suggest that the impaired integrity of the cerebral blood vessels in ApoE4 subjects is due to canonical Wnt pathway deactivation. The research program aims to dissect the role of canonical Wnt pathway in regulating the structural and functional integrity of cerebral blood vessels in the normal adult brain, investigate regulation of the pathway during the process of normal ageing, and characterize the role of ApoE variants in regulating canonical Wnt pathway in cerebral blood vessels. This research program will significantly contribute to the acquisition of a substantial knowledge in the field of cerebrovascular biology by providing new insights into the mechanisms involved in maintaining the integrity of the cerebral blood vessels in the adult brain.