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

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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.