Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Molecular Medicine

Major Professor

Jun Tan, Ph.D.

Co-Major Professor

Huntington Potter, Ph.D.

Committee Member

Susan Pross, Ph.D.

Committee Member

Andreas Seyfang, Ph.D.

Committee Member

R. Douglas Shytle, Ph.D.

Keywords

Secretase, APP, EGCG, Luteolin, Diosmin

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of ß-amyloid (Aß) peptides as plaques in the brain. Central to this AD pathology is mismetabolism of the amyloid precursor protein (APP). Recent studies suggest that flavonoids, a class of secondary plant metabolites, may be useful for the prevention and treatment of a variety of neurodegenerative diseases. The studies detailed herein, investigate the ability of two such classes of flavonoids, green tea derived catechins and 5,7-dihydroxyflavones, to modulate APP metabolism in "Swedish" mutant APP (APPsw) models of AD. Studies showed that green tea derived (-)-epigallocatechin-3-gallate (EGCG) effectively reduced Aß generation and resultant amyloidosis both in vitro and in vivo. In concert with these findings, EGCG markedly promoted non-amyloidogenic APP proteolysis via activation of the putative a-secretase, a-disintegrin-and-metalloprotease-10 (ADAM10). Furthermore, luteolin and various related 5,7-dihydroxyflavones, effectively reduced Aß generation and resultant amyloidosis both in vitro and in vivo, as well. Data revealed that luteolin decreased amyloidogenic γ-secretase APP proteolysis via presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Elucidation of these flavonoids' cellular/molecular mechanisms also revealed their potential for opposing neurofibrillary tangle (NFT) pathology, another hallmark of AD. These data raise the possibility that flavonoid administration to AD patients may prove to be viable and effective prophylactic strategy.

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