Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Stephen Pasternak

2nd Supervisor

Dr. Shawn Whitehead

Joint Supervisor

Abstract

Alzheimer’s Disease (AD) is characterized by Beta-Amyloid (Aβ) plaques within the brain. Aβ peptides are produced by the cleavage of Amyloid Precursor Protein (APP). Our lab has previously discovered a novel pathway for APP internalization mediated by ADP-ribosylation factor 6 (Arf6). This pathway resembles macropinocytosis, transporting cell surface APP directly to lysosomes, a possible site for Aβ production. We set out to characterize the effectors downstream of Arf6. In SN56 and N2A cells we co-transfected HA-tagged APP (to label cell-surface APP) with compartment markers, to visualize APP trafficking. We used dominant negative and constitutively active mutants, pharmacological inhibitors, and siRNA for Rac1, Cdc42, and RhoA to determine their roles in APP macropinocytosis. APP trafficking to lysosomes was reduced after knockdown of Rac1, Cdc42, and RhoA, and inhibition of this transport reduced production of Aβ40 and Aβ42. Our findings indicate a role for Rac1, Cdc42, and RhoA in Aβ production.

Available for download on Monday, January 01, 2018


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