Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Michael H.B. Stowell

Second Advisor

Harald Junge

Third Advisor

Michael Klymkowsky

Fourth Advisor

Marvin Caruthers

Fifth Advisor

Robert McLeod

Abstract

Alzheimer's disease is a devastating neurodegenerative syndrome that afflicts tens of millions of patients worldwide for which no effective therapy or prevention currently exists. Although the disease mechanisms remain elusive, it is clear that the 42 amino acid β-amyloid peptide is of central importance. The present work has combined structural, biochemical and in vivo analyses to uncover a catalytic role for the major synaptic vesicle protein synaptophysin in neurotransmitter release. We have found that this catalytic activity is directly targeted and inhibited by the beta-amyloid peptide causing synaptic dysfunction early in the progression of Alzheimer's disease. The novel method developed to analyze neurotransmitter release kinetics at individual synapses constitutes a significant improvement in sensitivity, accuracy and reproducibility over currently popular methods. Finally, biophysical studies were carried out to isolate and characterize truncated synthetic byproducts of beta-amyloid which inhibit its aggregation dynamics and neurotoxicity, leading to the identification of two candidates showing great promise as therapeutic agents in the fight against Alzheimer's disease.

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