Year of Publication

2009

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Arts and Sciences

Department

Chemistry

First Advisor

Dr. D. Allan Butterfield

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL). The proteins were consistent with AD pathology and have been central to further investigations of the disease. The present study was focused on the identification of specific targets of protein S-glutathionylation in AD, early AD (EAD), and mild cognative impairment (MCI) using a redox proteomics approach. In AD IPL we identified deoxyhemoglobin, α-crystallin B, glyceraldehyde phosphate dehydrogenase (GAPDH), and α-enolase as significantly S-glutathionylated relative to these brain proteins in control IPL. Both, GAPDH and α-enolase were also shown to have reduced activity in the AD IPL. With further investigation gammaenolase, dimethylarginine dimethylaminohyrdolase (DDAH), Cathepsin D, and 14-3-3 gamma were identified as significantly S-glutathionylated in the EAD IPL. Alpha enolase was also identified as significantly S-glutathionylated in MCI IPL. These results provide a correlation in proteins S-glutathionylated in the progression of AD even in the reversible conditions of amnestic MCI.

Amyloid beta-peptide (1-42) [Aβ(1-42)], one of the main component of senile plaque, can induce in vitro and in vivo oxidative damage to neuronal cells through its ability to produce free-radicals. The aim of this study was to investigate the protective effect of the xanthate, D609, on Aβ(1-42)-induced protein oxidation using a redox proteomics approach. D609 was recently found to be a free radical scavenger and antioxidant. In the present study, rat primary neuronal cells were pretreated with 50 μM of D609 followed by incubation with 10 μM Aβ(1-42) for 24 hours. In the cells treated with Aβ(1-42) alone four proteins that were significantly oxidized were identified:

Glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase, malate dehydrogenase, and 14-3-3 zeta. Pretreatment of neuronal cultures with D609 prior to Aβ (1-42) protects all the identified oxidized proteins in the present study against Abeta(1- 42)-mediated protein oxidation. Therefore, D609 may ameliorate the Aβ(1-42)-induced oxidative modification.

Included in

Chemistry Commons

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