Project Summary Cerebral blood vessels are critical to deliver oxygen and nutrients to the brain, and to remove carbon dioxide and other waste products. Although just 2% of the body’s weight, 20% of the circulation is directed to the brain, highlighting the importance of the cerebral vasculature to the health and function of the brain. Blood vessels that vascularize the central nervous system (CNS) harbor distinct physical, transport, metabolic, and signaling properties, termed the blood-brain barrier (BBB). Manifested within the endothelial cells (ECs) that line the lumen of the CNS vasculature, these BBB properties stringently regulate the movement of molecules, ions, and cells between the blood and the brain, allowing for proper neuronal function and safeguarding the neural tissue against injury and disease. As such, many neurological diseases are associated with BBB disruption, including multiple sclerosis (MS), epilepsy, and stroke. Recently it has been suggested that BBB dysfunction may contribute to the pathogenesis of Alzheimer’s disease (AD); however, the extent, nature, and contributions of this dysfunction to AD pathophysiology remains enigmatic. To identify nuanced changes to the brain vasculature in AD, a vascular-specific proteomic approach was employed. This approach revealed down-regulation of many enzymes involved in fatty acid and lipid biosynthesis, namely ELOVL fatty acid elongase 7 (ELOVL7), in the cortical vasculature of AD patients compared to controls. From here, this proposal will test the hypothesis that aberrant vascular lipid metabolism is a critical component of AD pathophysiology. Many classes of lipids have been implicated in regulating the trafficking and proteolytic activity of disease-relevant enzymes in AD. As lipid signaling is critical to brain homeostasis, vascular integrity, and AD etiology, identification of the lipidomic changes occurring at the BBB during AD could give important insight about the pathogenesis of AD and potentially identify novel therapeutic targets that can be used to normalize the BBB in AD patients. While ELOVL7 has never been studied in brain ECs or in the context of AD, previous studies have revealed that ELOVL7 is uniquely enriched in brain ECs in both mice and humans. Further, brain EC-specific transcriptomic approaches have shown dynamic loss of ELOVL7 expression in neuroinflammatory mouse models with known BBB disruption. Data such as these, taken together with the finding that ELOVL7 is decreased in the brain vasculature of patients with AD, steers this proposal towards the hypothesis that ELOVL7 may be critical to BBB function and that its downregulation may contribute to AD etiology. This hypothesis will be tested in vivo by conditional deletion of ELOVL7 within brain ECs of mice. Understanding the role of ELOVL7 at the BBB may elucidate crucial mechanisms of AD pathophysiology, and its downstream fatty acid metabolites may prove to be viable therapeutics to normalize the br...