Defense Date

2009

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmacology & Toxicology

First Advisor

Guo-Huang Fan

Second Advisor

Michelle Block

Third Advisor

Kurt Hauser

Abstract

Mounting evidence indicates an involvement of inflammation in the pathogenesis of Alzheimer’s disease. While there are other mechanisms involved, it is this role of inflammatory processes that we wish to investigate. Triptolide is the major constituent in the Chinese herb, Tripterygium wilfordii Hook F, and has been used for centuries as part of Chinese herbal medicine. The four ringed structure has close homology to drugs of the steroid class and it has been shown to be beneficial as an anti-inflammatory for rheumatoid arthritis and for treatment of certain cancers. The aim of this study was to evaluate the potential therapeutic effect of Triptolide on the neuropathology and deficits of spatial 6 learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) doubletransgenic mice, a well established Alzheimer’s disease (AD) mouse model. After treatment of APP/PS1 mice with Triptolide (40μg/kg, three times weekly,), initiated when the mice were 5 months old, for as little as 8 weeks, significant decrease in β-amyloid (Aβ) deposition and microglia activation was observed. Moreover, Triptolide treatment robustly rescued spatial memory deficits observed in APP/PS1 mice. However, APP processing, tau hyperphosphorylation, and the activities of the two major kinases involved in tau hyperphosphorylation, cyclin dependent kinase 5 (cdk5) and glycogen synthase kinase 3β (GSK3β) were not affected by the Triptolide treatment. Based on the recent finding for the inhibitory effect of Triptolide on Aβ-induced production of pro-inflammatory cytokines from microglia, we propose that Triptolide treatment may have beneficial properties in halting glial activation and help restore an immune system that fights plaque deposition. Although the exact mechanism of action has yet to be deduced, the increase in APP CTFs while having a significant decrease in amyloid plaque deposition suggests that alterations in gamma secretase activity may be a possible answer. Currently, these results support the use of Triptolide as an effective therapeutic to prevent the progression of Alzheimer’s disease.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

July 2009

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