2024 New Investigator Awards Program (NIAP)
Unveiling the Neurovascular Responses to Amyloid-Beta Antibodies
How can beta-amyloid antibody therapies be made more effective?
Wonjae Lee, Ph.D.
Duke University
Durham, NC - United States
Background
Beta-amyloid is a sticky protein fragment that forms abnormal clumps called plaques in the brain, a key hallmark of Alzheimer’s. Researchers have worked to develop antibody therapies that use the body’s immune system to target and remove beta-amyloid plaques. Some of these therapies have shown amyloid-clearing abilities in clinical trials and have been approved by the FDA. However, these therapies do not consistently improve clinical outcomes, having only modest effects on slowing cognitive decline. Additionally, antibody therapies may cause complications such as vascular (blood vessel) inflammation and disruption of a specialized structure known as the blood-brain barrier (BBB). The BBB helps maintain a healthy brain environment by tightly regulating what goes in and out of the brain from the circulating blood.
Dr. Wonjae Lee and colleagues believe that beta-amyloid antibodies are generally unable to cross an intact BBB, but they worsen vascular inflammation, which leads to a disruption in the BBB that allows them entry into the brain. While BBB disruption may help beta-amyloid antibodies reach the brain and clear beta-amyloid plaques, it may also be harmful overall to the brain, counteracting the therapeutic benefits of antibody therapy.
Research Plan
The research team will study the effects of beta-amyloid antibodies on brain-blood vessel interactions and BBB disruptions using a model system using human cells called the Neurovascular Unit-on-a-Chip (NVU chip). The NVU chip models a functional neurovascular unit, which is composed of different brain cells, including nerve cells and glia cells (support cells in the brain), and blood vessels of the brain. Using NVU chips, Dr. Lee and colleagues will study how brain-blood vessel interactions change in response to different types of beta-amyloid antibodies, different stages of Alzheimer’s (with differing amounts of BBB disruption), and genetic differences. Finally, the researchers will test the effects of delivering beta-amyloid antibodies using biological vehicles that can penetrate the BBB without disrupting it.
Impact
The findings may suggest ways to personalize and improve existing therapeutic strategies for Alzheimer’s. In addition, the results may support the NVU chip platform as a powerful model for precision medicine in Alzheimer’s and related dementias.
The New Investigator Program Award (NIAP) is jointly funded by the Alzheimer's Association and National Alzheimer’s Coordinating Center.