Date of Award
Doctor of Philosophy (PhD)
Michael H.B. Stowell
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.
Adams, Daniel Jack, "Catalysis of Neurotransmitter Release is a Target of Alzheimer’s Disease: Etiologic Mechanism and Novel Therapeutic Potential" (2013). Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations. 26.