Examining macropinocytosis regulation and its role in Alzheimer's Disease
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.