2023 Alzheimer's Association Research Grant (AARG)
Reprogramming Endothelial Cells to Prevent and Treat Alzheimer Disease
Could targeting stress in cells prevent abnormal build-up of proteins in Alzheimer’s?
Camilla Ferreira Wenceslau, Ph.D.
University of South Carolina
Columbia, SC - United States
Background
As the body ages, the cells that line blood vessels undergo changes that can cause them to stiffen. If left uncontrolled, this could contribute to heart disease. One change that these cells undergo is known as endothelial-to-mesenchymal transition (EndMT). Research suggests that problems with a structure found in cells known as the endoplasmic reticulum may underlie EndMT.
The endoplasmic reticulum serves as the protein-making “factory” inside cells. Stress to the endoplasmic reticulum can cause it to release modified or “misfolded” proteins, which could include abnormal beta-amyloid and tau protein, two hallmark brain changes in Alzheimer’s. More research is required to understand the relationship between endoplasmic reticulum stress, EndMT, and proteins found in Alzheimer’s.
Research Plan
Dr. Camilla Ferreira Wenceslau and colleagues will use animal models to test whether endoplasmic reticulum stress can lead to EndMT, and whether this causes cells to make proteins that contribute to brain changes seen in Alzheimer’s. The researchers will study genetically engineered mice that are modified to either develop heart disease or Alzheimer’s-like brain changes. The researchers will collect blood vessels from the mice and test their function and health, and measure levels of any proteins released by cells that line the blood vessels. Dr. Ferriera Wenceslau will also look for biological markers, or “biomarkers,” of EndMT in these cells, to understand when during heart or Alzheimer’s disease this important cellular change may occur.
The researchers will also test strategies to prevent EndMT in the mice. They will provide the mice with a treatment that prevents endoplasmic reticulum stress and determine whether this alleviates beta-amyloid and tau production. The researchers will also genetically engineer the mice to develop high levels of proteins that might reverse EndMT. Their goal is to test whether these strategies might prevent or decrease changes in blood vessels that might contribute to heart or Alzheimer’s.
Impact
This project could identify novel therapeutic strategies to prevent proteins from being misfolded during Alzheimer’s or other brain diseases. Results could be used to inform studies in humans, including clinical trials testing medications designed to prevent endoplasmic reticulum stress and restore healthy protein production in Alzheimer’s.