2023 Endolysosomal Activity in Alzheimer’s (E2A)
Organelle contact sites as determinants of endolysosomal activity in AD
Do problems in the waste disposal system of brain cells contribute to Alzheimer’s?
Paola Pizzo, Ph.D.
University of Padua
Padova, Italy
Background
Cells throughout the body have a complex system to remove any waste or unwanted products When a protein is damaged or no longer needed, a bubble-like vesicle compartment within the cell, called an autophagosome, will engulf the protein, then carry it to an enzyme-containing vesicle called a lysosome. When a lysosome contacts an autophagosome, the two vesicles fuse and protein breakdown begins. Problems with this waste disposal pathway may promote a toxic build-up of proteins, such as beta-amyloid (a hallmark brain change in Alzheimer’s) within brain cells.
Research Plan
Dr. Paola Pizzo and colleagues are developing probes that can detect contact between vesicle compartments, including lysosomes and autophagosomes.. These probes work by binding to different kinds of vesicles, and emitting light when the probes get close to each other. The probes work rapidly and are reversible, which means they can emit light multiple times as vesicles interact and disconnect.
The researchers will use these probes, combined with microscopy, to examine this pathway in various cell models. They will do this using cells collected from both humans and genetically-engineered Alzheimer’s like mice that either have Alzheimer’s related brain changes or are cognitively unimpaired. . Differences in how the probes respond with or without Alzheimer’s brain changes may point to problems in the waste disposal pathway in Alzheimer’s.
Impact
By pinpointing altered steps in this pathway, the results from this study will offer up novel therapeutic strategies that could stave off neurodegeneration in Alzheimer’s.