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Title page for ETD etd-11182005-151111


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
  • neurofibrillary tangle
  • tau
  • post translational modification
  • Alzheimer's disease -- Molecular aspects
  • Oxidation Physiological
  • Cytoskeletal proteins
  • 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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