Type of Document	Dissertation
Author	Boutte, Angela Monique
URN	etd-11182005-151111
Title	CYTOSKELETAL PROTEIN DYSFUNCTION AND OXIDATIVE MODIFICATION IN ALZHEIMER’S DISEASE
Degree	PhD
Department	Neuroscience
Advisory Committee	Advisor Name Title Elaine Sanders-Bush Committee Co-Chair Thomas J. Montine Committee Co-Chair John Oates Committee Member Michael McDonald Committee Member Olivier Boutaud Committee Member William Valentine Committee Member
Keywords	Cytoskeletal proteins Oxidation Physiological Alzheimer's disease -- Molecular aspects post translational modification tau neurofibrillary tangle plaque amyloid beta aging
Date of Defense	2005-08-23
Availability	unrestricted
Abstract Our aged population is poised to expand dramatically within the next decade. In Alzheimer’s disease (AD) pathogenesis studies, the end point hallmarks or lesions are known and well studied; however, the exact processes leading to these lesions are not. Defining early pathological events at the molecular and protein level and targeting appropriate therapies to pre-clinical or early stage dementia is necessary to avert the coming public health crisis. This project showed that lipid peroxidation products can lead to microtubule dysfunction that is characteristic of AD and that this is associated with their accumulation on tau from among the cytoskeletal proteins investigated. In contrast, another type of protein oxidation was observed selectively on Beta-III tubulin using mass spectrometry. Together, these data indicate that multiple oxidative modifications to cytoskeletal proteins are likely occurring in AD and that these can contribute to cytoskeletal dysfunction, leading to a modified model of AD pathogenesis. Furthermore, the results suggest that approaches to limit protein oxidation may have the downstream effect of suppressing protein insolubility and its consequences. Perhaps, with further investigation, studies will be able to define drug-treatable targets to prevent and slow neurodegenerative disease progression.
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