2023 Alzheimer's Association Research Fellowship (AARF)

Mechanism of Mitochondria-Targeted AD Therapeutics in Human Brain Cells

How might targeting the powerhouses of brain cells impact Alzheimer’s-related brain changes?

Thi Kim Oanh Nguyen, Ph.D.
Mayo Clinic
Rochester, MN - United States

Background

Alzheimer’s is associated with hallmark brain changes including the build-up of the proteins beta-amyloid and tau into abnormal plaques and tangles, respectively. Alzheimer’s is a complex disease and there are other brain changes that occur. Recent studies suggest that specialized structures inside cells called mitochondria — the powerhouse of energy generation for the cells — may also undergo damage early on in Alzheimer's, before the development of plaques and tangles. 

Dr. Thi Kim Oanh Nguyen and colleagues recently developed therapeutic compounds that target mitochondria. When administered to genetically engineered Alzheimer’s-like mice, these compounds seemed to improve brain changes associated with Alzheimer’s.

Research Plan

Building on this research, Dr. Nguyen and colleagues will study their novel compounds in a specialized type of stem cell collected from adult human tissue called iPSCs (induced pluripotent stem cells). iPSCs can be programmed to grow into any type of cell in the body. The researchers will study iPSCs grown into brain nerve cells, microglia (the brain’s primary immune cells), and astrocytes (a type of helper cell in the brain). They will compare cells that have a genetic variation associated with increased Alzheimer’s risk in some populations called APOE-e4 to cells without this genetic variation, APOE-e3. 

Dr. Nguyen and colleagues will use advanced cellular biology and chemistry techniques to study the development of Alzheimer’s-like brain changes in these cells, including the build-up of beta-amyloid and tau and mitochondrial function. Then they will investigate how administration of their mitochondria-targeting compounds impacts these Alzheimer’s-associated changes.

Impact

If successful, this project may lead to the development of new therapeutics that target mitochondria to treat or prevent Alzheimer’s.