Blood-brain-barrier (BBB) dysfunction is a key feature of Alzheimer’s disease (AD), but the underlying molecular changes associated with this dysfunction are not well understood. A group of researchers, including FunGen-AD researchers Caghan Kizil, Richard Mayeux, and Badri Vardarajan from Columbia University, focused on pericytes and astrocytes of the gliovascular unit (GVU), cells that support the integrity of blood vessels in the brain. Studies of these cells in human tissue and animal models revealed that SMAD3 and VEGFA expression in brain vascular cells was altered in AD.
Researchers conducted single-cell RNA sequencing on GVU pericytes and astrocytes in human brain tissue. The sequencing results showed that, in AD, SMAD3 is upregulated in pericytes, and VEGFA is downregulated in astrocytes. These results were validated in external datasets with sequencing data for thousands of pericyte and astrocyte nuclei. Experiments using pericytes derived from human induced pluripotent stem cells (iPSCs) showed that VEGF treatment decreases SMAD3 expression; blocking VEGF signaling increases SMAD3 expression. Columbia investigators validated these results in a zebrafish model of AD. This study underscores the critical role of pericytic SMAD3 and astrocytic VEGFA interactions in BBB dysfunction, highlighting potential therapeutic targets for AD.
This research, partially supported by FunGen-AD grants R01AG067501 and RF1AG066107, is published in Nature Communications here. You can read more about these research findings at the following links:
- Unique Signatures Discovered: New Mayo Clinic Research Reveals Molecular Clues to Alzheimer’s Disease (SciTechDaily, PressNewsAgency, Pedfire)