2023 Endolysosomal Activity in Alzheimer’s (E2A)
Understanding microglial lysosomal biology in Alzheimer's disease
Does the brain’s waste disposal system malfunction in Alzheimer’s?
Soyon Hong, Ph.D.
University College London
London, United Kingdom
Background
Microglia are the primary immune cells that serve as one of the first defenses against nerve cell damage. Microglia sense and help maintain a healthy brain by removing unwanted or damaged components. This waste disposal system is also responsible for removal of disease related molecules such as beta-amyloid (a hallmark brain change in Alzheimer’s) and damaged connections between brain cells. Understanding how microglia take up, process, and degrade cellular waste will clarify the role microglia play in Alzheimer’s.
Research Plan
Dr. Soyon Hong and colleagues will study how microglia operate in genetically engineered Alzheimer’s-like mice. Their experiments will focus on compartments within cells called lysosomes, which contain enzymes that can digest waste. Using methods that can specifically isolate proteins from lysosomes in microglia, the team will compare the resulting collection of proteins between cognitively unimpaired mice and mice that develop Alzheimer’s-like brain changes. This comparison will identify the proteins that are most altered through Alzheimer’s.
The researchers will then compare the observed changes in protein levels from the previous experiment to changes observed in another model of Alzheimer's. To do this, the team will study a specialized type of stem cell collected from adult human tissue called human induced pluripotent stem cells (hiPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes. Using specialized microscopy, the researchers will examine whether the proteins identified in the mouse models are altered in amount or location in the human microglia cells.
Impact
The results of this study will be key to understanding the basic operation of the waste disposal system in brains developing signs of Alzheimer’s. The proteins identified could provide potential targets for therapeutic pathways.