Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Pasternak, Stephen
Abstract
The subcellular compartment known as the lysosome has been shown to play a critical role in the pathogenesis of Alzheimer’s disease. It has been linked to fundamental pathogenic mechanisms, including the cleavage of amyloid precursor protein and the aggregation of both amyloid-beta and tau. Understanding the mechanisms that drive the delivery of cell surface and extracellular proteins to the lysosome is critical to understanding the role of the lysosome in the development and progression of Alzheimer’s disease. Previous studies have shown that the rapid, actin-dependent endocytic mechanism known as macropinocytosis can deliver amyloid precursor protein, amyloid-beta aggregates, and tau aggregates to lysosomes. However, macropinocytosis remains understudied in neurons, and its regulation has yet to be elucidated. Here, I demonstrated that macropinocytosis regulators, including Arf6 and the Rho GTPases Rac1, Cdc42 and RhoA, govern he uptake of amyloid precursor protein, along with amyloid-beta oligomers and tau fibrils in neuronal cell lines and human cortical neurons. I also demonstrate that proposed APP ligands reelin, NGF and oligomeric amyloid-beta also drive macropinocytosis of APP, and this brings them in contact with the beta and gamma secretases. These results provide new insights into a previously under-explored cellular mechanism and its role in a highly prevalent disease and suggests that this mechanism could be a fruitful new avenue to explore novel therapeutic approaches for the treatment of Alzheimer’s disease.
Summary for Lay Audience
Alzheimer’s disease is a progressive neurodegenerative disease and the most common form of dementia, currently affecting over 500,000 Canadians. The disease typically begins with difficulties remembering and maintaining attention, eventually progressing to experiencing problems carrying out tasks of daily life and requiring full-time care. One of the major causes of the disease involves the production and accumulation of aggregated protein in the brain which results in dysfunction and death of the cells responsible for brain function. The progressive nature of this disease is due to the spread of these toxic aggregated proteins across the brain. The events in the cells of the brain which lead to the production of these toxic aggregates and the spread of them from cell to cell are unknown. Identifying the specific mechanism which causes this could pose an attractive new target to develop treatments for this disease. The work conducted in this thesis aims to identify the role a cellular mechanism called macropinocytosis, also referred to as ‘cell drinking’, plays in the production of one of these aggregates, and in the uptake of toxic aggregates into cells. By demonstrating this, future work can try to evaluate the potential for targeting this mechanism to prevent or reduce the production and spread of toxic protein aggregates in Alzheimer’s disease.
Recommended Citation
Krupa, Jordan M., "Examining macropinocytosis regulation and its role in Alzheimer's Disease" (2024). Electronic Thesis and Dissertation Repository. 10295.
https://ir.lib.uwo.ca/etd/10295