Award Date

5-1-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Committee Member

Jefferson W. Kinney

Second Committee Member

Laurel Pritchard

Third Committee Member

Joel Snyder

Fourth Committee Member

Frank Van Breukelen

Number of Pages

128

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is unknown. Recent studies have implicated alterations in calcium homeostasis as a pathogenic contributor to AD. Calcium dysregulation has been observed in aged and AD brains, an event which could potentially facilitate the development of multiple pathologies observed in AD. Specifically, disrupting intracellular calcium levels in vitro has been demonstrated to increase amyloid-beta (Aβ) production, tau phosphorylation, and neuronal loss. However, there is a paucity of data on the behavioral and biochemical consequences of chronic in vivo perturbation of calcium homeostasis. In a series of experiments designed to evaluate the effects of chronic calcium dysregulation, we chronically administered different dosages of ryanodine or thapsigargin directly into the lateral ventricles at a minimal flow rate via Alzet osmotic minipumps. To investigate interactions with neuroinflammation, a common occurrence in AD, experiment 3 examined the effects of an acute inflammatory response on chronic calcium dysregulation. Learning and memory was examined in multiple paradigms including the Morris water maze and novel object recognition. Results indicate chronic alterations in calcium regulation produced deficits in the water maze and novel object recognition task following six weeks of central infusion. Analyses of protein levels revealed that there may be neurochemical changes consistent with AD following chronic calcium dysregulation. The induction of neuroinflammation combined with calcium dysregulation produced similar deficits. The data suggest that altered neural calcium handling may play a significant role in AD. Additionally, these data may shed light on the role of calcium regulation in learning and memory.

Keywords

Alzheimer's disease; Calcium; Calcium – Metabolism – Regulation; Calcium in the body; Learning and memory; Ryanodine; Thapsigargin

Disciplines

Medical Neurobiology | Neuroscience and Neurobiology | Neurosciences

Language

English


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