Understanding How Human Blood-Brain Barrier Cells Drive Alzheimer's Disease

We seek to understand how Alzheimer’s disease risk variants dysregulate human brain vascular cells to compromise brain health.

The risk for late-onset Alzheimer’s disease (AD) involves dozens of risk variants operating in diverse cell types. Elucidating the functions of these risk variants is critical to inform treatments but is challenging, in part because the vascular half of human brain cell types has eluded powerful single-cell assays. We will use our new vascular-capturing VINE-seq technique to comprehensively determine the cells and genes dysregulated AD variants. We will then use our bioorthogonal labeling approaches to determine how AD variants dysregulate brain vascular transport functions to promote AD risk.

We will apply two of our newly developed molecular approaches in our proposal: (1) VINE-seq to efficiently isolate vascular cell types from postmortem human brain tissue; and (2) bioorthogonal proteome labeling to understand the functions of vascular Alzheimer’s disease risk variants.

Upon study completion, we will significantly expand our understanding of how Alzheimer’s disease (AD) genetic variants dysregulate human brain vascular cells to drive AD risk. These data will enable new functional studies investigating the mechanisms by which brain barrier cells contribute to neurodegenerative disease.