Researchers at the University of California, San Diego School of Medicine and the Institut Pasteur identified a protein that when over-expressed, leads to an increased generation of amyloid ß (Aß). This protein called RANBP9 appears to facilitate the process by which enzymes cleave amyloid precursor protein (APP) into amyloid beta peptide.
The team was studying low-density lipoprotein receptor-related protein (LRP), a protein that shuttles Aß out of the brain and across the blood-brain barrier to the body, where it breaks down into harmless waste products. A small segment of LRP can also stimulate Aß generation, and the scientists narrowed this section down to a 37 amino acid stretch.
“RANBP9 is one of the proteins we identified that interacted with this LRP segment, but one that had never before been associated with disease-related neuronal changes,” said David E. Kang, Ph.D., assistant professor of neurosciences and director of this study, which appears in the May 1 issue of the Journal of Biological Chemistry. “We discovered that this protein interacts with three components involved in Aß generation: LRP, APP, and BACE1.”
RANBP9 appeared to scaffold them into a particular structure, Dr. Kang reports. He explains that these three components must come together to result in the first cleaving of APP, which leads to production of Aß.
To test this, the scientists knocked out RANBP9 in the cell. They discovered that 60% less Aß was produced. The researchers' next step is to verify these findings in animal models.