2024 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)
A novel bispecific antibody targeting amyloid beta
Could a new antibody treatment target toxic proteins in Alzheimer’s without an unwanted immune response?
Jose Henrique Ledo, Ph.D.
Medical University of South Carolina
Charleston, SC - United States
Background
The proteins beta-amyloid and tau accumulate to form plaques and tangles respectively, the two hallmark brain changes observed in Alzheimer's. Researchers have worked to develop antibody therapies that use the body’s own immune system to target and remove amyloid plaques. Some of these therapies have shown amyloid-clearing abilities in clinical trials and have been approved by the FDA.
However, such treatments have also been shown to increase the risk of developing negative side effects known as amyloid-related imaging abnormalities (or ARIA). This can be due to accumulation of beta-amyloid near brain blood vessels and these accumulations are associated with increased stiffening of the vessels. When vessels are stiffer, it can be difficult for muscle cells in the blood vessels to properly pump blood, possibly restricting blood flow throughout the brain. This process is known as “cerebral amyloid angiopathy” or CAA and is a risk factor for developing ARIA. Research suggests that ARIA occurs most often in people who have a variation in a gene associated with Alzheimer’s, called APOE4, or people who are receiving high-dose antibody treatment. The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. There are several variations of the APOE gene, including APOE-e2, APOE-e3 and APOE-e4. The APOE-e4 variation is thought to impact some populations’ risk of developing Alzheimer’s
Dr. Jose Henrique Ledo and colleagues have developed a new antibody, called AbE4, that shows promise for targeting harmful clumps of beta-amyloid protein in the brain without causing an unwanted immune response, which could help people with APOE4 variations.
Research Plan
Dr. Ledo and team will test AbE4 in genetically engineered Alzheimer’s-like mice that have different variations in the APOE gene, including APOE4. Using these mice, they will determine whether AbE4 will impact the uptake of beta-amyloid by microglia, the brain’s primary immune cell. The research team will also study whether AbE4 can reduce the harmful buildup of beta-amyloid protein and decrease the risk for CAA and subsequently ARIA. Further, they will also explore whether AbE4 may prevent an unwanted immune response.
Impact
Results from this study could help better understand the development of ARIA and lead to novel therapies that target toxic protein clumps in Alzheimer’s. This treatment may also prevent ARIA in people at genetic risk for this side effect.