2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)
Restoring Depalmitoylation in Alzheimer’s Disease Cellular and Mouse Models
What biological mechanisms contribute to the build-up of beta-amyloid plaques in the brain?
Skarleth Cardenas Romero, Ph.D.
Beth Israel Deaconess Medical Center
Brookline, MA - United States
Background
The endo-lysosomal pathway is a series of structures inside brain cells that are responsible for breaking down and disposing of cellular waste. Studies have shown that the endo-lysosomal pathway becomes damaged in brain diseases, including Alzheimer’s, and this damage may hinder the brain’s ability to clear abnormal proteins, such as beta-amyloid plaques and tau tangles, two hallmark brain changes associated with Alzheimer’s, that accumulate during disease.
Genes play an important role in Alzheimer’s, but for most individuals who have late-onset Alzheimer’s (the most common form of the disease), the genetic mechanisms are complex and not well understood. Dr. Skarleth Cardenas-Romero and colleagues have identified multiple genes associated with changes in the endo-lysosomal pathway in Alzheimer’s, suggesting that variations in these genes may increase the risk of developing late-onset Alzheimer’s.
Based on their preliminary studies, Dr. Cardenas-Romero and team believe that a protein named palmitoyl-protein thioesterase 1 (PPT1) regulates how beta-amyloid is processed in the endo-lysosomal pathway and may contribute to the build-up of beta-amyloid plaques in Alzheimer’s.
Research Plan
The researchers will first study how PPT1 contributes to beta-amyloid clearance in a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). iPSCs can be re-programmed to grow into any type of cell in the human body, including nerve cells. For this study, the research team will develop iPSCs from individuals with Alzheimer’s. They will study the effects of decreasing and increasing the activity of PPT1 on endo-lysosomal pathway function and beta-amyloid accumulation in these cells.
Next, Dr. Cardenas-Romero and colleagues will study genetically engineered Alzheimer’s-like mice with reduced PPT1 activity. These mice typically have a build-up of beta-amyloid plaques and a reduced lifespan. The research team will increase PPT1 activity in the brain of these mice and determine how it impacts beta-amyloid accumulation and other biological brain changes associated with Alzheimer’s.
Impact
The results of this study may shed light on genetic factors influencing how beta-amyloid accumulates in the brains of individuals with Alzheimer’s and other neurodegenerative diseases. The findings may suggest new therapeutic targets for treating biological brain changes associated with Alzheimer’s.