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Advisory Committee Chair

John J Shacka

Advisory Committee Members

Mathieu J Lesort

Vithal K Ghanta

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder and the most common form of dementia. Fundamental hallmarks of AD include progressive hippocampal neuron death, neurofibrillary tangles associated with tau deposits, and accumulation of amyloid plaques containing amyloid beta (Aß), a cleavage product derived from amyloid precursor protein (APP). Deficits in the clearance of APP, due to lysosomal dysfunction for instance, result in the accumulation of APP C-terminal fragments (APP-CTFs) and toxic species of Aß (Aß40-42) (1). Defective lysosomal proteolysis represents a mechanism that may contribute to AD pathologies, including protein aggregation and neuronal cell death. Therefore the lysosome represents an important target to identify novel therapeutics that promote clearance of APP. Bafilomycin (BafA1) is a macrolide antibiotic that binds to and effectively inhibits the C-subunit (ATP6V0C) of vacuolar-type ATPase (V-ATPase) at high concentrations (2, 3). This results in a decrease in vesicular acidification that is associated with an inhibition of autophagy-lysosome pathway (ALP) function and leads to robust cell death (2, 3), in addition to the accumulation of APP-CTFs (4). In contrast, we have shown previously that low concentrations of BafA1, too low to inhibit V-ATPase, attenuate neuronal cell death resulting from treatment with the lysomotropic agent chloroquine (CQ) (5, 6), in a manner consistent with preservation of the ALP (5, 6). However, whether "low-dose" BafA1 or its binding subunit ATP6V0C, can be targeted to regulate the clearance of APP remains to be elucidated. In this study, we show that a low concentration of BafA1 attenuates APP-CTF accumulation, an observation also associated with preservation of ALP function. Notably, BafA1 attenuated CQ-induced neuronal cell death, a protective effect that we show to be ATP6V0C-dependent. In addition, we show that ATP6V0C over-expression attenuates BafA1-induced neuronal cell death and accumulation of APP-CTFs, effects which were exacerbated when ATP6V0C was knocked down. Together these results support our hypothesis that both BafA1 and ATP6V0C may play an important, protective role in regulating the effects of neuronal cell death via toxic stimuli. Furthermore, maintenance of the ALP by BafA1 at low concentrations may be an effective means of decreasing the accumulation of APP and in turn AD-associated pathogenesis.

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