Graduation Year

2009

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Molecular Medicine

Major Professor

Huntington Potter, Ph.D.

Co-Major Professor

Samuel Saporta, Ph.D.

Committee Member

Jun Tan, M.D., Ph.D.

Committee Member

Ronald Keller, Ph.D.

Committee Member

Craig Doupnik, Ph.D.

Committee Member

Eric Bennett, Ph.D.

Committee Member

Eric Bennett, Ph.D.

Keywords

neurodegeneration, intracranial, intrathecal, inflammation, and microglia

Abstract

Neurodegeneration describes the progressive loss of structure and function of neurons, leading ultimately to cell and organism death. Although the initiating factors of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Amyotrophic Lateral Sclerosis may be different, they share common pathophysiologies. Proteinopathies, as these diseases are now termed, are characterized by atypical deposits of proteins, often due to misfolding. Associated with these deposits are dysfunctional mitochondria, oxidative stress, disrupted axonal transport, inflammation, and apoptotic cell death. If this occurs in motor neurons, as in ALS, ataxia precedes death with little or no change in cognition. On the other hand, if the deposits are found in cortical neurons, as in Alzheimer’s disease, the outcome is dementia and motor function remains largely intact. Each disease is selective for particular types of neurons and brain regions. Although research has elucidated much of the molecular biology involved in these diseases, their initiating causes remain largely unknown.

Most of our current understanding originated with the identification of gene mutations that cause rare familial forms of these diseases. As a result, numerous strains of transgenic animals have been developed to study neurodegenerative disease phenomena and were central to the studies presented in this body of work. Novel routes of drug and gene delivery are described here as well as characterization of the mouse models studied. In particular, this work demonstrates that the blood brain barrier is

disrupted in ALS followed by the formation of autorosettes in ALS mice. In various Alzheimer’s disease mouse models, it was demonstrated that the acute phase reactant alpha-1-antichymotrypsin (ACT) not only interacts with amyloid plaques, but also induces tau phosphorylation

in vivo; tying together these disease hallmarks. It was also shown that small fragments of Aβ (1-11) could disrupt the formation of mature amyloid plaques in these mice. Lastly, it was demonstrated that mature plaques could also be decreased by intracranial delivery of granulocyte-macrophage stimulating factor (GM-CSF). My dissertation research goal was to understand and develop these treatment strategies based on protein disaggregation, neuroprotection, and inflammation, meanwhile developing novel methods for targeted delivery of molecules into the CNS of mice.

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