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Dissertation
NMDA glutamate receptors in Alzheimer's disease
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Sep 2001
DOI:
https://doi.org/10.17918/00009291
Abstract
Alzheimer's disease (AD) is a multi-faceted disease that affects several neurotransmitter systems and a number of brain regions. The hippocampus, which is affected early in the disease process, is of particular interest based on observations that some hippocampal subregions and more specifically, certain cell populations within these subregions, are more vulnerable to cell death than others. While the underlying cause of this specific vulnerability is not clearly understood, excitotoxicity, mediated via ionotropic glutamate receptors, may play a crucial role. Moreover, the repertoire of glutamate receptors expressed on neurons may influence this glutamate-mediated vulnerability. Therefore, it is hypothesized that perturbations of glutamate receptor subunits may contribute significantly to the viability of the cell. N-methyl-D-aspartate (NMDA) receptor subunits were examined in subregions of the AD hippocampus in patients representing a broad range of AD pathology (mild, moderate, severe groups) using both biochemical and in situ hybridization techniques. Importantly, both protein level and mRNA expression of NR1, NR2A, and NR2B subunits were examined in the same groups of patients. Protein levels and mRNA expression for NR1 were significantly reduced in the hippocampus between patient groups. Further post hoc analysis showed a significant reduction of mRNA expression in the CA4 subregion of the hippocampus while the protein level was reduced in the subiculum. NR2B protein level and mRNA expression were reduced in moderate and severe AD groups. The NR2A subunit mRNA expression and protein level did not change throughout the disease. Cellular analysis of gene expression by grain density counts revealed a change only in NR2A subunit and showed a significant increase in the moderate group compared to mild and severe groups. This investigation provides evidence to support the hypothesis that an alteration in expression of NMDA receptor subunit may render it more vulnerable to glutamate excitotoxicity.
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Details
- Title
- NMDA glutamate receptors in Alzheimer's disease
- Creators
- Amanda Eberz
- Contributors
- David M. Armstrong (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- ix, 110 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888914904721