Alzheimer’s disease (AD) is a debilitating chronic neurodegenerative disease that is the leading cause of dementia and involves memory loss, disorientation, language issues, and many other behavioral abnormalities. Recently it has been suggested that dysfunction of blood vessels in the brain may contribute to the onset and progression of this devastating disease. Despite the potential importance, very little is known about how the blood vessels of the brain actually change in patients with AD and how these changes affect disease pathology. To understand how cerebral blood vessels change in patients with AD, Dr. Daneman’s team performed mass spectrometry-based proteomics to compare the molecular composition of brain microvessels in patients with AD versus age/sex-matched controls. Remarkably, they found a downregulation of a series of lipid metabolic enzymes in the brain microvessels from AD patients, including a down-regulation cerebrovascular fatty acid elongation. This raises the hypothesis that downregulation of brain vascular fatty acid metabolism may play a role in the vascular dysfunction that is observed in patients with AD.
In this project, Dr. Daneman’s team aims to identify the role of brain vascular fatty acid metabolism in regulating the brain’s drainage systems, neuroinflammation and neurodegeneration. In preliminary studies they have generated an endothelial (EC)-specific knockout of the key fatty acid elongator, Elovl7, which they observed to be downregulated in the brain microvessels from patients with AD. They found EC-specific deletion of Elovl7 led to alterations in both the lipidome of the vessels themselves and of the brain parenchyma. Interestingly, loss of vascular Elovl7 led to an increase in neural phosphatidylserine (PS) levels, lipids that act as ‘eat me’ signals for dying cells. Therefore, they hypothesize that loss of brain vascular fatty acid metabolism may indeed play a role in the neurodegenerative processes observed in patients with AD, by priming neural cells for cell death. In this proposal they plan to further analyze the role of brain vascular fatty acid metabolism, aiming to identify whether loss of this fatty acid metabolism primes the brain for neurodegeneration, how brain vascular fatty acid metabolism regulates the drainage systems of the brain, and elucidate the mechanisms that regulate brain vascular fatty acid metabolism in health and disease. The ultimate goal is to determine whether targeting brain vascular fatty acid metabolism may be therapeutic for AD.
