All ETDs from UAB

Advisory Committee Chair

Gail V W Johnson

Advisory Committee Members

Richard S Jope

Mathieu J Lesort

Elizabeth S Sztul

Bradley K Yoder

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

eimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two major pathophysiological hallmarks, beta-amyloid (A��) plaques and tau tangles. In AD and other tau associated neurodegenerative disorders, termed tauopathies, a critical role in promoting neuronal degeneration has been demonstrated for hyperphosphorylated forms of tau. Recent findings suggest that cleavage of tau in the carboxyl-terminal region (Asp421) may also promote deleterious effects of tau on neuronal health. In the first half of my study, the relationship between Asp421 cleaved tau and a common AD associated stressor (endoplasmic reticulum [ER] stress) was investigated using an inducible cortical neuronal model. Cells expressing Asp421 tau presented with higher levels of toxicity as compared to cells expressing the full-length protein, even before induction of ER stress. Under ER stress conditions, toxicity was significantly enhanced in Asp421 tau expressing cells. The differences in toxicity were underscored by alterations in caspase activation and cytokine signaling. In the second study, the effect of Asp421 tau expression on mitochondrial function was examined. Mitochondria in cells expressing Asp421 tau showed a shortened and rounded morphology, suggesting fragmentation. Additionally, mitochondrial function was severely inhibited in these cells as demonstrated by mitochondrial membrane potential loss and decreased calcium buffering ability in iv response to elevated intracellular calcium levels. Further, mitochondria in Asp421 tau cells exhibited increased levels of reactive oxygen species (ROS). Taken together the results suggest that Asp421 tau may negatively impact mitochondrial functioning in affected neurons in AD and other tauopathies, and promote disease progression. Given the importance of proper mitochondrial functioning in maintaining neuronal health, further studies are warranted in order to fully elucidate the mechanisms underlying this toxicity.

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