Perlecan domain V prevents amyloid-beta toxicity : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2012]
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| Subjects: |
| Abstract: | ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia among elderly individuals, accounting for approximately 60 to 80 percent of dementia cases. Symptoms include difficulty remembering names, depression, confusion and impaired judgment. The extracellular deposition of amyloid-beta protein and intraneuronal generation of neurofibrillary tangles are neuropathologic hallmarks of AD. As many risk factors for AD are vascular in origin (e.g. high blood pressure, atherosclerosis, heart disease), and blood vessel defects in clearing Abeta from the brain are probable key components of AD pathology, my research has focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the proteoglycan perlecan. Our previous data has shown that the proteolytically cleaved C-terminal fragment of perlecan, Domain V, prevents Abeta-induced cortical neuronal cell death in vitro in an alpha2beta1 integrin dependent manner. To investigate the molecular mechanisms responsible, my dissertation focuses on the Abeta neurotoxic signaling pathway which occurs through the interaction of Abeta with the alpha2beta1 and alphavbeta1 integrins and ends with the activation of c-Jun. We hypothesized that DV prevents or changes the interaction of Abeta with neurons, altering intracellular signaling pathways, and ultimately blocking neuronal death. I demonstrate that DV inhibits the activation of neurotoxic and/or apoptotic signaling molecules known to be involved in executing neurotoxicity and apoptosis in both cortical and hippocampal neurons. In addition to evaluating DV's effects on Abeta toxicity in vitro, I also evaluated the ability of administered DV to prevent the buildup of amyloid plaques in the brains of an AD mouse model that has been genetically modified to overexpresses a human amyloid precursor protein (APP) transgene (PDAPP). Previous work showed that DV could inhibit Abeta deposition in vitro. Therefore, we hopothesized that administered DV could prevent the deposition of Abeta in vivo. I show that administration of recombinant DV does not lessen Abeta deposition in the brain under our experimental parameters. Finally, I show that DV inhibits Abeta toxicity in brain microvascular endothelial cells and restores function in an alpha5beta1 integrin-dependent manner. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of the Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2012." Approved as to style and content by: Gregory J. Bix, Sarah E. Bondos, L. Gerard Toussaint, Irene Griswold-Prenner, Geoffrey Kapler. |
| Physical Description: | xiii, 125 leaves : illustrations (some color) ; 28 cm. |
| Bibliography: | Includes bibliographical references. |