Files and links (1)
PDFOpen Access (License Unspecified), Open Access
Dissertation
Sonic Hedgehog Signaling Pathway in Amyloid Precursor Protein Trafficking and Proteolysis
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2014
DOI:
https://doi.org/10.17918/etd-6998
Abstract
Alzheimer's disease (AD) is the most common form of dementia for which there is no cure. AD is characterized by progressive neurotoxicity resulting in cell death and cognitive decline. Two hallmarks responsible for the aforementioned neuropathology are senile plaques and neurofibrillary tangles composed of Amyloid-Beta; (A-Beta) peptide and hyperphosphorylated tau protein, respectively. A-Beta; is produced from regulated proteolysis of Amyloid precursor protein (APP). Alterations to this process can results in increased A-Beta; deposition resulting in AD pathogenesis. Here we discovered that cyclopamine, a plant sterol, modulates APP metabolism by altering APP subcellular trafficking. Cyclopamine treatment alters retrograde trafficking of APP C-terminal fragments (CTFs) after endocytosis, thereby decreasing A-Beta; generation. This raises the possibility that cyclopamine may ameliorate AD-like pathologies in other AD animal models. We addressed the possibility that cyclopamine's target, Smoothened (Smo), can alter APP metabolism and discovered a likely novel regulatory role for Smo. Smo is a component of the Sonic hedgehog (Shh) signaling pathway, which requires the primary cilium for canonical mammalian Shh signaling. Pharmacological and genetic analysis lead us to believe several Shh signaling components modulate APP proteolysis via a previously uncharacterized noncanonical Shh mechanism. Collectively these findings lead us to investigate the possibility that APP colocalizes with Shh signaling components to the primary cilia and whether or not primary cilia respond to extracellular A-Beta; levels. We discovered APP colocalized with Smo to primary cilia and that primary cilia were significantly compromised upon A-Beta; treatment. Collectively, this thesis provides significant insight into APP proteolysis through regulating trafficking events. Modulating APP trafficking opens a novel avenue to address A-Beta; production. In addition, we discovered a novel target for AD therapeutics; the Shh signaling pathway.
Metrics
43 File views/ downloads
17 Record Views
Details
- Title
- Sonic Hedgehog Signaling Pathway in Amyloid Precursor Protein Trafficking and Proteolysis
- Creators
- Anna Gennadiy Vorobyeva - DU
- Contributors
- Aleister Saunders (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 208 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 6998; 991014632239704721