Understanding How Newly Approved Anti-Amyloid Drugs Affect Blood Vessels

The aim of this project is to determine what underlies the cerebrovascular side effects of newly approved anti-amyloid-beta immunotherapies for Alzheimer’s disease.

With the positive news of U.S. Food and Drug Administration approval of anti-amyloid-beta antibody treatments, or immunotherapies, comes the downside of side effects. ARIA, which stands for amyloid-related imaging abnormalities, is a well-known phenomenon associated with these treatments and reflects damage to blood vessels in the brain. How this damage arises and how to prevent or treat it remain unclear.

Kate Emily Foley, PhD, and her colleagues aim to fill in some gaps in this knowledge by evaluating how microglia and astrocytes, which are immune and support cells in the brain, respond to these immunotherapies. For their work, they will sequence RNA molecules that each cell produces in response to acute or chronic exposure to the therapy. These state-of-the-art sequencing tools will reveal how cells react even before ARIA develops.

With this information in hand, Dr. Foley and coworkers will focus on a protein that adversely affects the brain’s blood vessels. This protein, called matrix metallopeptidase 9, or MMP9, offers a target that could be manipulated to reduce ARIA. Lab models that lack the gene for MMP9 may show less activation of the process that leads to immunotherapy-related ARIA. To confirm this possibility, the researchers will work with lab models and with postmortem tissue samples to assess how MMP9 affects the brain’s blood vessels.

The results are expected to generate important information about pathways that could be targeted in cells to slow or prevent ARIA in people receiving antibody therapy.

The use of single cell sequencing combined with IHC validation to parse out the specific signals that microglia and astrocytes are producing in response to anti-Aß antibodies has not been done. Additionally, we propose a unique mechanism by which MMP9 facilitates anti-Aß antibody mediated cerebrovascular compromise, and aim to correct it by utilizing a genetic KO of MMP9.

From this study we will have a better idea how the brain is responding to anti-Aß antibodies that results in cerebrovascular compromise and ARIA. We will also have tested a mechanism by which ARIA risk may be extrapolated, and if MMP9 is found to cause worsened cerebrovascular outcomes after anti-Aß antibody treatments, we will be able to test for MMP9 levels in humans via plasma or CSF to re-evaluate their ARIA risk.