Mechanisms of Vascular Dysfunction in Alzheimer’s Disease

The blood-brain barrier (BBB) plays a vital role in maintaining health of the brain by strictly regulating blood-flow and the entry of nutrients and oxygen. Disruption of this BBB and dysfunction of the endothelial cells has been previously linked to a number of neurodegenerative diseases, including Alzheimer’s Disease (AD). Due to the limited efficacy of therapeutics that target the AD-related peptide Amyloid-Beta (Aβ), new methods and molecular pathways for investigating cerebrovascular dysfunction are required. The first approach presented in this thesis is integrating endothelial cells into established stem cell derived brain organoid protocols in order to foster the development of a vasculature. We found that adding endothelial cells to the extracellular matrix and supplementing the organoid media with vascular endothelial growth factor was sufficient for generating cerebral orgaonids with contiguous, three-dimensional vasculature-like structures that stained positive for CD31, an endothelial marker. We next utilized mouse models of AD to determine how Aβ deposition effected endothelial barrier function and transcriptional profile. We found there was a direct positive correlation between Aβ deposition and vascular leakiness, as well as an increase in type I interferon antiviral signaling. We found that activating type I interferon signaling in endothelial cells decreased VE-cadherin expression and increased vascular permeability. Following this, we investigated Amyloid-induced disruption of WNT/β-catenin signaling in brain endothelial cells. We found that Amyloid-Beta reduced both endogenous and WNT-stimulated β-catenin signaling, as well as endothelial barrier function. This effect was consistent across brain endothelial cells and stem cell derived endothelial cells.