Role of C99 in the Lipid Dyshomeostasis in Alzheimer's Disease

Background Lipids (fats) are important for nerve cell health and function. Lipids help control many nerve cell functions, including how nerve cells communicate. Many proteins help balance lipid levels inside nerve cells- a process called lipid “homeostasis.” This often occurs inside specialized areas within nerve cells called MAMs (mitochondria-associated endoplasmic reticulum membranes). Preliminary results from Dr. Jorge Montesinos’ study suggests that a portion of amyloid precursor protein (APP, the parent protein of beta-amyloid), called “C99” accumulates in MAMs both in nerve cells in the laboratory dishes and in tissues from individuals who had Alzheimer’s disease. Past studies show that people with Alzheimer’s disease have problems associated with lipid balance inside their nerve cells. The connection between APP and lipid balance is not entirely clear, but lipid imbalance can harm nerve cell function. Research Plan Dr. Montesinos proposes to investigate how “C99”, may contribute to lipid imbalances inside nerve cells during Alzheimer’s disease. Dr. Montesinos’ team will use different models for the study, including cells and tissues donated by people who had Alzheimer’s disease, and a special type of stem cell called induced pluripotent stem cells (iPSCs) from adult skin tissue. Since iPSCs can be reprogrammed into any cell type in the human body, the researchers will use these iPSCs to create nerve cells in laboratory dishes. The researchers will alter C99 levels in these different models to understand C99’s role in how specific lipids are created inside nerve cells. This will help Dr. Montesinos understand mechanisms that may underlie problems with lipid metabolism (breakdown or storage of fats for energy) and balance in the presence of beta-amyloid. Next, the researchers will test how increased C99 in MAMs contributes to other changes in nerve cells characteristic of Alzheimer’s disease. The ultimate goal of the project will be to evaluate lipid changes in laboratory models of Alzheimer’s disease, by understanding how C99 interacts with lipids inside MAMs. Impact This project proposes to study a novel biological pathway that may contribute to nerve cell damage during Alzheimer’s disease. If successful, the study results will provide new information to help explain how nerve cells become damaged during Alzheimer’s disease, and reveal ways to restore imbalances in fat levels in nerve cells in order to preserve nerve cell function.