Advisory Committee Chair
Qin Wang
Advisory Committee Members
Alecia K Gross
Lori L McMahon
Erik D Roberson
Thomas Van Groen
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Through widespread efferent projections, the locus coeruleus-noradrenergic (LC-NA) system supplies the cerebral cortex with norepinephrine, a key modulator of cognition. Neurodegeneration of the LC is an early hallmark of Alzheimer’s disease (AD), but despite this profound neuronal loss, there are several studies that show that NE levels actually remain stable or even elevated, especially at early stages of the disease. This indicates that the overall integrity of the NA system, rather than a loss of NE, is likely contributing to AD pathogenesis. We previously showed that activation of the α2A adrenergic receptor (α2AAR) increases amyloidogenic processing of amyloid precursor protein (APP), and therefore increases amyloid β (Aβ) load in the brain. In this dissertation work, we sought to investigate α2AAR activity with AD advancement. We found an increase in α2AAR activity in the presence of Aβ in 2 independent AD mouse models. Importantly, human AD tissue samples showed an increase in G protein activation by α2AAR. Taken with our previous data showing that increased α2AAR activity leads to increased levels of Aβ, we have established a pathogenic positive feedback loop in which α2AAR promotes the generation of Aβ, and Aβ leads to increased activity of the α2AAR. We found that disrupting this loop by treating AD model mice with the α2AR antagonist idazoxan improved AD pathology and improved cognitive function. In addition to APP/Aβ regulating the α2AAR, we also found that APP regulates α2AAR trafficking and signaling. While APP has long been appreciated for its role in AD pathology, less is known about the physiological function of APP outside of AD. In this dissertation work, we identify a novel direct interaction between APP and the α2AAR that competes with arrestin 3 binding to the receptor. Accordingly, the presence of APP decreases α2AAR internalization and desensitization, which are arrestin-dependent processes. Our study provides the first evidence that APP fine tunes GPCR signaling and trafficking. These findings highlight the reciprocal regulation of APP and α2AAR.
Recommended Citation
Gannon, Mary Alana, "Reciprocal Regulation Of The Α2A Adrenergic Receptor And The Amyloid Precursor Protein" (2017). All ETDs from UAB. 1696.
https://digitalcommons.library.uab.edu/etd-collection/1696