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Dissertation/Thesis Abstract

Spin Labeled Fluorene Compounds are a Versatile Sword in the Fight Against Amyloid Beta Peptide of Alzheimer's Disease
by Hilt, Silvia, Ph.D., University of California, Davis, 2016, 162; 10182862
Abstract (Summary)

Amyloid-β (Aβ) peptide is generated after sequential cleavage of the constitutively expressed amyloid precursor protein (APP) by γ and β secretases, and is recognized as the primary causative agent underlying the neuropathogenesis of Alzheimer’sDisease (AD). Once generated, monomeric Aβ demonstrates a high propensity to aggregate into toxic Aβ oligomers (AβO) of various sizes, which eventually accumulate in the brain in the form of amyloid plaques. Mutations in either the gene for APP or one or both of its processing genes, presenilin-1 (PS1) and presenilin-2 (PS2) of the secretases complex leading to accumulation of Aβ and early-onset familial AD. Late onset AD is modulated by mutations in the gene for apolipoprotein E (apo-E), with the isoform apo-E4 leading to an approximate eight-fold increase in risk for AD, and by environmental and life style factors. The Alzheimer’s disease process develops over decades, with substantial neurological loss occurring before a clinical diagnosis of dementia can be rendered. A major roadblock to the management of AD is the inability to definitively diagnose AD until post-mortem examination. It is therefore imperative to develop methods that permit safe, early detection and monitoring of disease progression. Magnetic resonance imaging (MRI) is a non-invasive way to detect and monitor AD progression and therapy, but so far MRI contrast has been obtained only using Gd(III) based contrast agents. Fluorene compounds have garnered attention as amyloid imaging agents. Our lab has developed a spin labeled fluorene (SLF) compound that contains a fluorene moiety with known affinity for Aβ and a pyrroline nitroxyl spin-label moiety. We hypothesized that the SLF compound will specifically coat assemblies of amyloid beta in the brain and, by establishing a boundary of magnetic field inhomogeneity, produce MRI contrast in tissues with elevated levels of the Aβ peptide. I found that labeling of brain specimens with the SLF compound produces negative contrast in samples from AD model mice whereas no negative contrast is seen in specimens harvested from wild-type mice. Injection of SLF into live mice resulted in good brain penetration, with the compound able to generate contrast 24-hr post injection. (Abstract shortened by ProQuest.)

Indexing (document details)
Advisor: Voss, John C.
Commitee: Coleman, Matthew, Jin, Lee-Way, Rutledge, John
School: University of California, Davis
Department: Biochemistry and Molecular Biology
School Location: United States -- California
Source: DAI-B 78/03(E), Dissertation Abstracts International
Subjects: Neurosciences, Biochemistry, Medical imaging
Keywords: Alzheimer's disease, Amyloid beta oligomer, Cd spectroscopy, Magnetic resonance imaging (mri) contrast, Mp-spr, Spin-labeled fluorene
Publication Number: 10182862
ISBN: 978-1-369-31177-8
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