Date of Award

1-1-2014

Embargo Period

1-1-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Kumar Sambamurti

Abstract

Accumulation of the amyloid β (Aβ) protein in the brain as senile plaques is a signature lesion of Alzheimer's disease (AD). The mechanisms of Aβγ accumulation that foster its deposition is a subject of intense study and represent the primary targets for most drug development efforts in the field. As one of the most important neurodegenerative diseases in the world, it is imperative that we continue to move toward efficacious treatment strategies. A number of y-secretase inhibitors (GSIs), such as N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), have been developed with the goal of reducing Aβ to treat AD. Although most studies show that DAPT inhibits Aβ in a dose-dependent manner several studies have also detected a biphasic effect with an unexpected increase at low doses of DAPT. In this thesis, we confirm the increase in Aβ40 and Aβ42 in SH-SY5Y human neuroblastoma cells treated with low doses of DAPT and identify one of the mechanisms for this paradox. Studies done in Chapter 2.2 add to the growing body of literature that suggest preserving γ-secretase activity, rather than inhibiting it, is important for prevention of neurodegeneration. Chapter 2.3 is aimed to characterize Aβ degradation pathways and examine intracellular Aβ40 (icAβ40) levels following inhibition of a number of proteolytic activities in our SHY-SY5Y cell culture model. Our data suggest that metalloproteinase(s) are major contributors to the turnover process at neutral pH, but a combination of protease inhibitors failed to substantially block the loss of AB occurring at acid pH, suggesting that uncharacterized activities other than the major lysosomal protease play a key role in degrading Aβ.

Rights

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