Dr. Daneman’s project focuses on the vascular cells that form part of the blood-brain barrier (BBB). Poor cardiovascular health and dysfunction in the brain’s vasculature increase the risk for or contribute to Alzheimer’s disease (AD). However, the specific molecular explanations for how BBB dysfunction is related to disease or whether vascular changes can cause Alzheimer’s pathologies remain undetermined. The Daneman lab is interested in filling this gap in knowledge. They recently began characterizing the differences in molecules produced by brain vascular cells in AD patients compared to healthy individuals. Their results implicate lipids, particularly a molecule called Elovl7, which was low in AD patients. Elovl7 is critical for the production of a diverse array of lipids that play crucial roles in supporting healthy functions.
In this project, the team is testing the hypothesis that the loss of Elovl7 in brain vascular cells impairs BBB function, which then contributes to Alzheimer’s-related pathologies, including inflammation and neurodegeneration. They proposed three experimental aims. In the first aim, they are testing whether the loss of Elovl7 in vascular endothelial cells negatively impacts the BBB and specific neurovascular functions in normal mice and exacerbates pathology in amyloid and tau mouse models. In the second aim, they are determining which lipids affect the inflammatory response of microglia and astrocytes and testing if supplementing mice with lipids generated by Elovl7 improves inflammation and other AD-related pathology in amyloid and tau models. For the third aim, they are exploring if changes in vascular lipid production also impair other brain entry and egress points, specifically those focused on in other Brain Entry and Exit consortium projects (glymphatic, ACE points, lymphatics, and choroid plexus).
At the end of the first year of funding, the team found that Elovl7-derived lipids are not essential for maintaining BBB structure or function. However, they do play a key role in regulating the brain’s response to inflammation. Loss of Elovl7 in vascular endothelial cells exacerbated hemorrhagic events and impaired the resolution of neuroinflammation, suggesting that Elovl7 helps protect the cerebral vasculature from systemic inflammatory signals. Moving forward, they will investigate how Elovl7 loss influences AD progression and test whether supplementing BBB lipids could mitigate neuroinflammation and strengthen brain vasculature.
