Life Sciences Commons^™

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 …

Cholinergic Enhancement Of Brain Activation In Mild Cognitive Impairment During Episodic Memory Encoding, Shannon L. Risacher, Yang Wang, Heather A. Wishart, Laura A. Rabin, Laura A. Flashman, Brenna C. Mcdonald, John D. West, Robert B. Santulli, Andrew J. Saykin

Publications and Research

Objective: To determine the physiological impact of treatment with donepezil (Aricept) on neural circuitry supporting episodic memory encoding in patients with amnestic mild cognitive impairment (MCI) using functional magnetic resonance imaging (fMRI).

Methods: Eighteen patients with MCI and 20 age-matched healthy controls (HC) were scanned twice while performing an event-related verbal episodic encoding task. MCI participants were scanned before treatment and after approximately 3 months on donepezil; HCwere untreated but rescanned at the same interval.Voxel-level analyses assessed treatment effects on activation profiles in MCI patients relative to retest changes in non-treated HC. Changes in task-related connectivity in medial temporal circuitry …

Proteolytic Cleavage Of Apolipoprotein E4 As The Keystone For The Heightened Risk Associated With Alzheimer’S Disease, Troy T. Rohn

Biology Faculty Publications and Presentations

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to …

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 …

Delayed Amyloid Plaque Deposition And Behavioral Deficits In Outcrossed Aβpp/Ps1 Mice, Brian A. Couch, Meghan E. Kerrisk, Adam C. Kaufman, Haakon B. Nygaard, Stephen M. Strittmatter, Anthony J. Koleske

School of Biological Sciences: Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid-β precursor protein (AβPP) and presenilin-1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. AβPP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 4–9 months of age. We crossed AβPP/PS1 animals with mice of a mixed genetic background (C57BL/6 × 129/SvJ) and investigated the development of AD-like features in the resulting outcrossed mice. The onset of memory-based behavioral impairment …

Aβ Alters The Dna Methylation Status Of Cell-Fate Genes In An Alzheimer’S Disease Model, Gary D. Isaacs, Noor Taher, Courtney Mckenzie, Rebecca Garrett, Matthew Baker, Nena Fox

Faculty Publications and Presentations

Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. We isolated the DNA from neurons treated with Aβ or vehicle, and digested the two samples with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto P. Nathan

Britto P. Nathan

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).

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 …

An Acute Inflammatory Response In A Diabetic Alzheimer’S Disease Model, Krystal Courtney D. Belmonte, Jefferson Kinney

McNair Poster Presentations

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 50 to 80 percent of all dementia cases. This neurodegenerative disease leads to neuronal death and tissue loss in the brain, resulting in the slow deterioration of memory, thinking skills, and eventually even the ability perform daily tasks. While it is not a normal part of aging, AD is mostly diagnosed in people over the age of 65; thus, the main risk factor for Alzheimer’s disease is increased age, though it is most likely other additional factors also contribute (Heese & Akatsu, 2006). Neuropathological hallmarks of AD include …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto P. Nathan

Faculty Research & Creative Activity

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).

Discovery Of Novel Cholinesterase Inhibitor (Rknu026) With P-Amyloid Aggregation Inhibitory Activity, Thippatai Hiranyaekaphap, Nitipol Srimongkolpithak, Thamrong Wongchang, Prayuth Poowaruttanawiwat, Kwanchai Rattanamanee, Ruengwit Kitbunnadaj

The Thai Journal of Pharmaceutical Sciences

No abstract provided.

Caspase-Cleaved Glial Fibrillary Acidic Protein Within Cerebellar White Matter Of The Alzheimer's Disease Brain, Troy T. Rohn, Lindsey W. Catlin, Wayne W. Poon

Biology Faculty Publications and Presentations

Although the cerebellum is generally thought of as an area spared of Alzheimer's disease (AD) pathology, recent evidence suggests that balance and mobility dysfunction may be magnified in affected individuals. In the present study, we sought to determine the degree of pathological changes within the cerebellum utilizing an antibody that specifically detects caspase-cleaved GFAP within degenerating astrocytes. Compared to control subjects, application of this antibody, termed the GFAP caspase-cleavage product (GFAPccp) antibody, revealed widespread labeling in cerebellar white matter with little staining observed in grey matter. Staining was observed within damaged astrocytes, was often localized near blood vessels and co-localized …

Isoform-Specific Effects Of Apoe On Neurite Outgrowth In Olfactory Epithelium Culture, Aseem Hussain, Minh Luong, Apryl Pooley, Britto Nathan

Faculty Research & Creative Activity

The apolipoprotein E4 (apoE4) genotype is a major risk factor for developing late-onset Alzheimer’s disease (AD). Inheritance of apoE4 is also associated with impairments in olfactory function in early stages of AD. In this project we examined the effects of the three common isoforms of human apoE (apoE2, apoE3, and apoE4) on neuronal differentiation and neurite outgrowth in explant cultures of mouse olfactory epithelium (OE).