Degree Type

Dissertation

Date of Award

1998

Degree Name

Doctor of Philosophy

Department

Theses & dissertations (Interdisciplinary)

Major

Neuroscience

First Advisor

Etsuro Uemura

Abstract

beta-amyloid is the primary protein component of neuritic plaques, which are degenerative foci in brains of patients with Alzheimer's disease (AD). The effects of this naturally occurring beta-amyloid on the cells of the central nervous system have not been completely understood. The effect of cytokines such as IL-1beta, TNF-alpha, and IFN-gamma on astrocytic nitric oxide is well documented; however, the effects of beta-amyloid on astrocytes for their cytokine-mediated release of nitric oxide are not established. In the present study astrocytic release of nitric oxide was studied following exposure to beta-amyloid peptide (beta25-35) in combinations with IL-1, TNF-alpha or IFN-gamma. None of the cytokines induced an increase in nitrite levels (nmol/mg protein) in astrocytic cultures by themselves. However, IFN-gamma combined with IL-1beta or TNF-alpha induced a significant increase in nitrite levels. Although both IL-1beta and TNF-alpha were effective costimulatory factors, the combination of IFN-gamma and IL-1beta was more effective in increasing nitrite levels in cultures than the combination of IFN-gamma and TNF-alpha. beta25-35 completely blocked the increase in nitrite levels by IFN-gamma and TNF-alpha, whereas beta25-35 partially blocked the effect of IFN-gamma and IL-1beta. These findings warrant a further study to determine how the modulatory action of beta-amyloid on cytokine-mediated astrocytic release of nitric oxide affects neuronal functions in AD patients. beta-amyloid increases the vulnerability of cultured neurons to glutamate-induced excitotoxic damage. Because astrocytes play a key role in uptake of extracellular glutamate and glutamate uptake is ATP dependent, we studied the effect of beta25-35 on glutamate and glucose uptake in cultured hippocampal astrocytes following 7 days of exposure to beta25-35. Glutamate uptake by control astrocytes was time-dependent. Astrocytes exposed to beta25-35, however, showed significantly lower glutamate uptake at all sampling times. Similarly, [14C] glucose uptake by astrocytes was inhibited by beta25-35. When glucose uptake was blocked by phloretin (10 mM), astrocytic [3H]glutamate uptake was also blocked, suggesting that the inhibitory effect of beta-amyloid on glutamate uptake is caused by diminished glucose uptake. Thus, our present study suggests a possible link among three proposed mechanisms of Alzheimer's disease: astrocytic nitric oxide release, global defect in cerebral energy metabolism and glutamate neurotoxicity.

DOI

https://doi.org/10.31274/rtd-180813-4967

Publisher

Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/

Copyright Owner

Aleksandra Parpura-Gill

Language

en

Proquest ID

AAI9826560

File Format

application/pdf

File Size

83 pages

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