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The Role Of Choline Acetyltransferase Variants In Alzheimer's Disease Models, Shawn Albers

Electronic Thesis and Dissertation Repository

The primate specific 82-kDa choline acetyltransferase (ChAT) isoform is found in the nuclei of cholinergic neurons, with a disruption in the subcellular localization in aging and AD brain samples# The functional significance of this protein is poorly understood. Previous studies have revealed a potentially protective role for 82-kDa ChAT, mediated through a reduction in amyloid-!1-42 (A!1-42) release in APP/PS1 double transgenic primary cortical neurons. Here we examine the effect of 82-kDa ChAT expression in transgenic neurons, on the amyloidogenic processing of amyloid precursor protein (APP) and A! production. In this study we demonstrate 82-kDa ChAT transcriptionally increases golgi- localized "-ear-containing …

Exploring The Structure And Biochemistry Of Oxidation-Mediated Inhibitation Of The Peptidyl-Prolyl Isomerase Pin1, Brendan T. Innes

Electronic Thesis and Dissertation Repository

Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that has been shown to be neuroprotective in aging-related neurodegenerative diseases such as Alzheimer's disease (AD). However, it is not active in AD brain, and a recent proteomic screen of Mild Cognitive Impairment (MCI) brain samples revealed that Pin1 is oxidized in the brains of these pre-AD patients. This suggests that this oxidation may be the cause of the loss of the neuroprotective Pin1 function in AD. The Pin1 active site contains a functionally critical cysteine residue (Cys113) with a low predicted pKa, making it highly susceptible to oxidation. We hypothesize that Pin1 is …

Contribution Of Trpm2 To Memory Loss In An Alzheimer's Mouse Model, Megan M. Chen

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive deterioration of memory and other intellectual abilities. Accumulation of amyloid-β (Aβ) peptide, the major contributor to the senile plaques central to AD, is thought to mediate neurotoxicity by inducing oxidative stress and calcium dysregulation. Transient Receptor Potential Melastatin type 2 (TRPM2) is a calcium permeable, non-selective cation channel activated under oxidative stress and ultimately induces cell death. The APPSWE/PSEN1ΔE9 double transgenic mouse model carries the human APPswe (Swedish mutations K594N/M595L) and PS1 mutations with a deletion in exon 9 (PS1-dE9), and is one of the most commonly used AD …

Biophysical Characterization And Cross-Seeding Properties Of Lfaos, Novel Prion-Like Oligomers Of The Amyloid-Beta Peptide Involved In Alzheimer’S Disease, Morgan C. Woodrow

Honors Theses

The amyloid-beta (Aβ) protein is known to play an important role in the etiology of Alzheimer’s disease (AD). Aβ peptide aggregates in the brains of AD patients to form soluble oligomers as well as insoluble fibrils. Oligomers of Aβ are now known to be the primary toxic agents in AD. Evidence is beginning to emerge regarding a conserved prion-like propagation mechanism in AD. One of the principal characteristics of prion diseases is their ability to self-propagate via a template-assisted-corruptive mechanism. Our lab has previously characterized a unique ‘Aβ prion’ called Large Fatty-Acid- Derived Oligomers (LFAOs). This project examines the ability …

Exploring The Interactions Between Interleukin-8 (Il8) And Amyloid-Β (Aβ) Peptide In Traumatic Brain Injury, Olivia G. Gibson

Honors Theses

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive dysfunction and memory loss, and pathologically characterized by amyloid-beta (Aβ) plaques and inflammation. Recent research has shown that these Aβ plaques are also found in traumatic

brain injury (TBI) patients. This discovery has led to a proposed pathway leading from traumatic brain injuries to dementia, more specifically AD. After a TBI, human granulin-A (GRN) and interleukin-8 (IL8) are released and the number of elastases in the brain increases in response to the inflammation response. IL8 is a cytokine that is released in acute inflammation responses, and the levels of IL8 …

The Cellular Nucleic Acid Binding Protein In Aging And Disease, Robin Webb

Theses and Dissertations--Molecular and Cellular Biochemistry

The ZNF9 gene on chromosome 3 encodes the cellular nucleic acid binding protein (CNBP), a ubiquitously expressed, 177 amino acid (≈19.5kDa) protein that is highly conserved among vertebrates. The function of the protein is largely unknown, however an expansion in the first intron of the protein results in myotonic dystrophy type 2 (DM2), a multisystemic disease featuring cardiac arrhythmia, muscle wasting, cataracts, and a range of neuropathologies. Remarkably, we recently discovered that CNBP is involved in regulating the activity of β-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-β peptide (Aβ). The progressive fibrillization …