Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

7-20-2011

Graduate Advisor

Michael R. Nichols, PhD.

Committee

Thiel, Teresa

Valerian D'Souza

Wendy Olivas

Abstract

Alzheimer's Disease (AD) is a progressive, neurodegenerative disorder which is ranked as a leading cause of death among Americans. AD is characterized by the presence of intracellular neurofibrillary tangles and extracellular plaques made of amyloid ß (Aß). Together these pathologies lead to severe memory impairment in patients, but research has implicated the presence of the Aß deposits as likely causes for AD progression. Aß is produced through the proteolytic cleavage of the integral membrane amyloid precursor protein, which occurs through the action of beta- and gamma-secretases and produces 39-43 amino acid Aß peptides. In AD, the Aß plaques are comprised of mostly 40 or 42 amino acid Aß (Aß(1-40) and Aß(1-42) respectively). Evidence suggests that in response to the presence of Aß in the brain, monocytic cells circulating in the blood are recruited across the blood brain barrier and transformed into brain macrophages, known as microglia. Here we investigate the ability of Aß to transform cultured THP-1 monocytes into macrophage-like cells as a model of the in vivo process. Our results indicate that an early-formed Aß oligomer, which is formed when Aß(1-42) is aggregated in water, has the ability to potently transform the non-adherent monocytes into adherent cells with many properties consistent with macrophages. Our data also shows that Aß(1-40) cannot form a species with a similar activity. We have determined that the transforming activity of Aß(1-42) occurs through formyl peptide receptor-like 1, but not through an NF-kappaB dependent mechanism. We also study the involvement of cAMP in a model system of cerebral amyloid angiopathy (CAA), a condition in which Aß deposits within the walls of cerebral vessels leading to hemorrhages. CAA occurs in many cases of AD, but especially in early onset AD cases. We studied the ability of cAMP to rescue human aortic vascular smooth muscle cells from Aß induced toxicity. We found that in our experiments treatment with some cAMP elevating compounds can subtly protect the cells from Aß. Overall we show that Aß is a peptide which has a wide variety of activities that are dependent upon the peptide assembly state.

Included in

Chemistry Commons

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