Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Alzheimer's disease (AD) and cerebral small vessel disease (SVD) frequently co-occur.
• Brain endothelial cells (BECs) express genes linked to AD genetic risk.
• Gene regulatory networks in neurovascular cells and their link to disease risk are understudied.

Purpose of the Study:

• Investigate noncoding genetic risk variants in neurovascular cells.
• Map enhancers and their target genes in different brain cell types.
• Understand the connection between gene regulation and AD/SVD.

Main Methods:

• Generated enhancer maps using CUT&Tag for H3K27ac and H3K4me3.
• Isolated cell type-enriched nuclei via fluorescence-activated nuclei sorting (FANS).
• Linked enhancers to target genes using promoter capture HiC and chromatin conformation data.

Main Results:

• AD heritability is linked to immune pathways, with some enrichment in BECs.
• SVD heritability shows broad enrichment across the neurovascular unit, including astrocytes.
• Amyloid processes are implicated in both AD and SVD; hypertension drugs may treat AD.

Conclusions:

• Neurovascular cells have distinct gene regulatory landscapes.
• Immune pathways are involved in AD heritability.
• SVD has broad neurovascular enrichment, suggesting potential therapeutic targets for both conditions.