2023 Alzheimer's Association Research Grant (AARG)
Mitophagy and amyloid pathology in Alzheimer's disease
How quality control of energy-producing organelles relates to brain changes associated with Alzheimer’s.
Heather Wilkins, Ph.D.
University of Kansas Medical Center Research Institute
Kansas City, KS - United States
Background
Mitochondria are specialized structures inside cells that act as the powerhouse of energy production for the cells. When mitochondria are damaged, the cell identifies and removes them through a quality control process known as mitophagy. When this process is not well regulated, damaged mitochondria can build up in brain cells impairing cognition and increasing beta-amyloid, a protein that accumulates to form the plaques observed in Alzheimer’s.
When scientists use chemical compounds to target and treat mitophagy dysfunction, they find a reduction in beta-amyloid plaques, as well as improvements in cognition. However, many of these chemical compounds do not specifically target mitophagy and can affect other processes in the body leading to harmful side effects. To improve this, more targeted approaches are needed. To develop these, it is important to understand mitophagy dysfunction in Alzheimer’s.
Research Plan
Dr. Heather Wilkins and team will determine how mitophagy dysfunction relates to appearance of beta-amyloid plaques by examining tissue from different sources: genetically engineered Alzheimer’s-like mice across different ages and progression of disease-like brain changes; special types of adult stem cells called iPSCs (inducible pluripotent stem cells) programmed to grow into different types of brain cells (astrocytes, neurons, and even groups of cells that act like a human brain); and tissue from individuals who had Alzheimer’s.
Dr. Wilkins will establish whether mitophagy dysfunction occurs in the mitochondria or in lysosomes (a specialized cell structure that helps the cell degrade waste and is part of the mitophagy pathway) and how this relates to beta-amyloid brain changes. By examining where in the cell mitophagy is disrupted, the researchers hope to develop targeted therapies to treat mitophagy dysfunction directly and with less harmful side effects.
Impact
This research will increase our knowledge of the specific impacts of mitophagy dysfunction on brain changes observed in Alzheimer’s, possibly leading to the development of targeted therapeutics.