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Dissertation
Chlamydia pneumoniae infection in human monocytes and brain endothelial cell: initiating factors in the development of Alzheimer's disease
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Mar 2002
DOI:
https://doi.org/10.17918/00010044
Abstract
This manuscript investigates the host-pathogen relationship leading to the entry of Chlamydia pneumoniae into the central nervous system through the blood-brain barrier. The endothelia of the blood-brain barrier and peripheral blood monocytes may be key components in controlling the entry of Chlamydia pneumoniae into the mammalian central nervous system. The purpose of this manuscript was to determine the effects of infection with Chlamydia pneumoniae on the endothelia surface adhesion molecules and junctional complexes important to the integrity of the blood-brain barrier. This study also has examined how infection of monocytes and endothelial cells affect [beta]-amyloid production and processing, possibly contributing to the angiopathy often associated with Alzheimer's disease. Infection of endothelial cells with Chlamydia pneumoniae stimulated changes in the expression of surface adhesion molecules, the release of substances affecting barrier permeability, and the production and processing of [beta]-amyloid. Likewise, infected monocytes have demonstrated increases in activation, expression of surface adhesion molecules, transmigration, and [beta]-amyloid processing and production. Our results have indicated that Chlamydia pneumoniae stimulated transendothelial migration of monocytes through the blood-brain barrier by increasing the expression of the surface molecules VCAM-1 and ICAM-1 on the endothelia, as well as LFA-1, VLA-4, and MAC-1 on monocytes. Infection of the blood-brain barrier resulted in changes in the tight junctional proteins occludin, and upregulation of [beta]-catenin, N-cadherin, and VE-cadherin in the zonula adherens. RT-PCR demonstrated an upregulation in the processing of [beta]-amyloid precursor protein mRNA in infected monocytes. SDS-PAGE/Western blot analyses, immunocytochemistry, and FACS analyses demonstrated upregulation of [beta]APP, [beta]1-40 and [beta]1-42 in monocytes and brain endothelial cells. These data suggest that infected endothelial cells facilitate trafficking of monocytes through the blood-brain barrier and contribute to local and systemic [beta]-amyloid processing associated with the angiopathy and pathology of Alzheimer's disease. In this way, infection at the level of the vasculature may play a role in the pathogenesis of Alzheimer's disease.
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Details
- Title
- Chlamydia pneumoniae infection in human monocytes and brain endothelial cell
- Creators
- Angela MacIntyre
- Contributors
- George P. Tuszynski (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
- xvi, 147 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021889010704721