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Basic Science and Pathogenesis.

Alexi Nott1

  • 1UK Dementia Research Institute, London, United Kingdom; Imperial College London, London, United Kingdom.

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Summary
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Alzheimer's disease (AD) heritability involves immune pathways, while cerebral small vessel disease (SVD) affects the entire neurovascular unit. Hypertension medications may treat AD, highlighting distinct gene regulatory networks in brain cells.

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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.