Date of Award
2011
Degree Type
Thesis
Degree Name
Master of Science
Program
Physiology
Supervisor
Dr. Stephen Pasternak
Abstract
Alzheimer’s disease (AD) is characterized by the deposition of Beta-Amyloid (AP) peptide plaques in the brain. Ap peptides are generated by the sequential cleavage of the Amyloid Precursor Protein (APP). The AP42 cleavage product is the most neurotoxic form. Previous studies in our lab have uncovered a novel rapid lysosomal APP trafficking pathway that bypasses the early and late endosomal compartments. We set out to characterize this transport pathway using APP constructs with an N-terminal HA-tag, allowing us to label APP at the cell surface with a fluorescently labeled antibody. SN56 cells and mouse cortical neurons were also co-transfected with fluorescently-tagged compartment marker proteins and a panel of endocytosis regulatory proteins bearing dominant negative and constitutively activating mutations. Rapid APP internalization to lysosomes is stimulated by antibody binding and is increased when Arfl activity was inhibited, but decreased when Arfó activity was inhibited. In addition, disruption of either Arfó or Arfl was able to significantly reduce Ap42 secretion into the media. Our findings suggest that rapid APP transport to lysosomes is regulated by Arfó and is an important, and potentially targetable, mechanism that regulates A(342 production, while Arfl regulates secretion of Ap42 into the media.
Recommended Citation
TANG, WEIHAO, "ARF6 CONTROLS LYSOSOMAL TRANSPORT OF APP AND Ap42 PRODUCTION" (2011). Digitized Theses. 3271.
https://ir.lib.uwo.ca/digitizedtheses/3271