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Doctoral Dissertation Announcement
Candidate: John J. Panos
Doctor of Philosophy
Title: Neurochemical Effects of Amyloid-Beta Oligomers in Rats
Dr. Lisa E. Baker, Chair
Dr. Alan Poling
Dr. Brad Huitema
Dr. James Cleary
Date: Monday, August 23, 2010 1:30 p.m. - 3:30 p.m.
3715 Wood Hall
Alzheimer’s disease is a progressive neurodegenerative disease associated with aging affecting millions of adults worldwide. The negative prognosis of this disease produces a burden on both society and family members of persons afflicted with Alzheimer’s disease. Although the symptomology of Alzheimer’s disease is well defined, the etiology of the disease is currently unknown.
The pathology of the disease has been associated with the formation of amyloid plaques (insoluble deposits of aggregated amyloid-β) that occur in the hippocampus, temporal, frontal, and parietal cortices of Alzheimer's disease patients. Recently, investigations of the small (low-n) soluble forms of amyloid-β have provided insight into progression of the associated neurotoxicity and cognitive dysfunction in Alzheimer’s disease. These investigations have led to the emerging and controversial hypothesis in Alzheimer’s disease research in which soluble amyloid-β oligomers are the primary cause of cognitive disruption and synaptic dysfunction in this progressive neurodegenerative disease (Walsh & Selkoe, 2004). Of interest are the naturally occurring amyloid-β oligomers secreted by cells expressing human amyloid-β precursor protein (APP). The 7PA2 Chinese hamster ovary (CHO) cell line is currently under investigation in our laboratory. The cell line referred to as 7PA2 is derived from CHO cells stably transfected with an APP751 cDNA expressing the V717F Alzheimer’s disease mutation. These cells contain amyloid-β monomers and SDS-stable amyloid-β oligomers including dimers and trimers, devoid of the larger insoluble amyloid-β aggregates.
The specific aim of this project was to investigate the neurochemical effects of direct intracerebral infusion of amyloid-β oligomers. Experiment 1 investigated direct infusions of cell-derived (7PA2) amyloid-β oligomers into the rat prefrontal cortex (PFC) while simultaneously conducting in vivo microdialysis to determine neurochemical efflux in the PFC. Immediately following microdialysis, cognitive dysfunction was tested using the novel object recognition test (NOR). Experiment 2 examined synthetic amyloid-β oligomer infusion in the PFC during microdialysis; post microdialysis NOR was also conducted. In both experiments, neurotransmitter concentrations in microdialysis samples were determined using HPLC-EC. These studies will aid in elucidating the mechanisms of action of low-n oligomers of amyloid-β and provide valuable information to researchers developing targeted therapeutics for Alzheimer’s disease acting on oligomers of amyloid-β.