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Dissertation
The GABA-A receptor in aging and Alzheimer's disease
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Dec 2001
DOI:
https://doi.org/10.17918/00009849
Abstract
The GABAA ([gamma]-aminobutyric acid) receptor is an integral component of mediating inhibitory neurotransmission in the adult brain via an intrinsic Cl- channel. Presently, it is unknown how alterations in the subunit composition GABAA receptors may contribute to altered drug responses or progression of neurodegenerative disease, such as Alzheimer's disease (AD). The investigations of this thesis strive to analyze several highly prevalent GABAA receptor subunits in the aged and AD brain. First, as an initial investigation into the GABAA receptor in the aged brain, protein levels of GABAA receptor subunits al and [beta]2/3 were examined in the hippocampus of young and aged non-human primates using immunohistochemical techniques. The results of this study demonstrated that the [beta]2/3 subunit was relatively unchanged between young and aged animals, while the [alpha]1 subunit was found to be reduced between these two groups. Next, two subsequent experiments were performed to assess the presence of both protein levels and mRNA expression of GABAA receptor subunits [alpha]1, [alpha]5, [beta]1, and [beta]2 in the AD hippocampus. The first study included subjects with a broad range of AD neuropathology (mild, moderate, and severe), as assessed by Braak stage classification. In this experiment, the [alpha]1, [beta]1 and [beta]2 subunits were found to be relatively unchanged with increasing AD pathologic severity. In contrast, the [alpha]5 subunit was found to be modestly, but significantly reduced (-13.5%) between pathologically mild patients and those with severe neuropathology within the CA1/CA2 and CA3 subregions. Finally, mRNA expression for those GABAA receptor subunits demonstrating alterations in protein levels (i.e. [alpha]5) were analyzed in patients with a broad range of increasing clinical severity of AD cognitive deficits. mRNA levels of both [alpha]1 and [alpha]5 were found to be modestly reduced between patients with no cognitive impairment (NCI) and patients with mild cognitive impairment (MCI). While [alpha]5 subunit mRNA expression was found to be further reduced that of the [alpha]1 subunit between NCI and MCI, and NCI and Probable AD patients, such reductions were not observed between MCI and Probable AD patient groups. (Abstract shortened by UMI.).
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Details
- Title
- The GABA-A receptor in aging and Alzheimer's disease
- Creators
- Robert Andrew Rissman
- 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
- xiii, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888881604721