2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)
Exploring the Physiological and Pathological Functions of BRI2 in Neurons
How does a protein important in the development of dementia affect nerve cell activity in the brain?
Metin Yesiltepe, M.D.
Rutgers Biomedical and Health Sciences
Newark, NJ - United States
Background
Studies show that variations in certain genes can increase or decrease a person’s risk of developing certain diseases, including the diseases that cause dementia. One gene of interest in dementia is known as ITM2B. The ITM2B gene encodes a protein, called integral membrane protein 2B or BRI2. This protein is found inside nerve cells (neurons). The protein helps protect the brain against the accumulation of beta-amyloid protein, which is a hallmark of Alzheimer’s. Variations in ITM2B can lead to shortened or altered versions of BRI2 that are not as effective at performing this important function. Variations in ITM2B may also affect the ability of nerve cells to function properly in the brain, but more research is required to understand how this occurs.
Research Plan
Using several laboratory models, Dr. Metin Yesiltepe and colleagues will characterize the role of the BRI2 protein in nerve cells. They will study how changes in the gene’s level of expression (high or low) affects nerve cell function in the brain. First, the researchers will study mice genetically engineered to lack BRI2 in one of two kinds of nerve cells: those that stimulate brain activity (known as “excitatory” neurons) and those that inhibit brain activity (or “inhibitory” neurons). The researchers will test learning and memory in these models, and study nerve and brain tissue samples collected. This will help Dr. Yesiltepe better understand exactly how a loss of BRI2 in the brain affects different kinds of nerve cell activity and overall brain function.
Dr. Yesiltepe’s team will also study BRI2 using a specialized type of cell called induced pluripotent stem cells (iPSCs). These stem cells are created from adult human skin cells and can be “reprogrammed” to turn into any cell in the body, including nerve cells. The researchers will generate iPSC-derived excitatory and inhibitory nerve cells that are missing the ITM2B gene (and therefore do not produce BRI2). By studying these nerve cells growing in laboratory dishes, the researchers will be able to better understand how a loss of BRI2 function directly impacts human nerve cells.
The research team’s proposed experiments offer several complementary approaches to comprehensively assess how certain variations in ITMB2 might influence nerve cell function.
Impact
This study will investigate a protein (BRI2) that helps protect the brain against changes that occur in Alzheimer’s. A deeper understanding of BRI2’s function could support research into ways to better preserve nerve cells during Alzheimer’s progression\, and open new avenues for potential therapies. Laboratory models created for this study could also be used by other researchers interested in studying the role of BRI2 in Alzheimer’s or other dementias.