The microtubule-associated protein tau forms pathological neuronal filaments in Alzheimer's disease (AD) and other neurodegenerative disorders, known collectively as tauopathies. Previous studies in transgenic mouse models of AD suggest that reducing tau expression may be safe and beneficial for the prevention or treatment of AD and possibly other tauopathies. As a first step toward identifying novel therapeutic strategies to reduce tau levels, the studies presented in this dissertation aim to investigate the role of the human tau 3'-untranslated region (3'-UTR) in regulating tau expression. Tau expresses two 3'-UTR isoforms, long and short, as a result of alternative polyadenylation. The exact sequence of these two 3'-UTR isoforms was determined by rapid amplification of cDNA 3'-ends (3'-RACE), and the two 3'-UTR isoforms were cloned into a luciferase reporter vector. Using these reporter constructs, the expression of these isoforms was found to be differentially controlled in human neuroblastoma cell lines M17D and SH-SY5Y by luciferase assays and quantitative PCR (qPCR). Through an unbiased screen of tau 3'-UTR deletions and fragments using luciferase reporter constructs, several regions in the long tau 3'-UTR isoform that contain regulatory cis-elements were identified. Additionally, several microRNAs were computationally identified as candidates that might bind the long tau 3'-UTR and thereby differentially control the expression of long versus short tau 3'-UTR isoforms. Screening these candidate microRNAs via luciferase reporter assay identified miR-34a, which was subsequently shown to repress the expression of endogenous tau protein and mRNA in M17D cells using Western blot and qPCR, respectively. Conversely, inhibition of endogenously expressed miR-34 family members leads to increased endogenous tau expression. Taken together, these studies suggest that the expression of the two tau 3'-UTR isoforms is differentially regulated and that this differential regulation is due to the presence of regulatory cis-elements found only in the long tau 3'-UTR isoform, including a binding site for miR-34 family members. Improved understanding of the regulation of tau expression by its 3'-UTR may ultimately lead to the development of novel therapeutic strategies for the treatment of Alzheimer's disease and other tauopathies.

Although molybdenum blue solutions have been known for more than twocenturies, an understanding of their chemical nature is only beginning to emerge.This dissertation aimed at elucidating the structural nature of the polydisperse,nanoscopic components in the solution phases and the solid states of partiallyreduced polyoxomolybdate (Mo-POM). The study offered at least fourcontributions to the area: (1) a rational protocol for the molecular recognition ofMo-POM with de novo organic hosts. (2) demonstration of kinetic precipitation ofa dynamic mixture of polyoxomolybdates and application of the technique to thestudy of the dynamic mixture by TEM (3) characterization of the Mo-POMnanostructures by an unusual combination of complementary analyticaltechniques. (4) a general approach for the synthesis of crown-ethers-containingtripodal molecules.The molecular recognition of Mo-POM with designer tripodal hexaminetris-crown ethers opened a window to the solution phase structures of Mo-POMnanoscopic components. Studies with a series of structurally analogous hostsprobed the relationship between the structure of the molecular host and theformation of nanostructures.An unusual combination of complementary analytical protocols: flow fieldflowfractionation, electron microscopy (transmission and scanning), andinductively coupled plasma – emission spectroscopy, was used to monitor thesolution-phase evolution of Mo-POM nanostructures. The crystallization – drivenformation of keplerate Mo-POM and solution-phase evolution of structurallyrelated nanoscopic species were apparent in the self-assembling process ofpartially reduced Mo-POM.

Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease. The key to understanding AD is to elucidate the pathogenesis of neuron degeneration in specific brain regions.We hypothesize that there is increased DNA oxidation in AD brain compared to age-matched control subjects, especially in mitochondrial DNA (mtDNA), and that the changes in DNA bases will affect protein expression in mitochondria and contribute to neurodegeneration in AD. To test this hypothesis:1) We quantified multiple oxidized bases in nuclear DNA (nDNA) and mtDNA of frontal, parietal, and temporal lobes and cerebellum from late-stage AD (LAD), mild cognitive impairment (MCI), and age-matched control subjects using gas chromatography/mass spectrometry with selective ion monitoring (GC/MS-SIM). Also, we quantified oxidized DNA bases in cortex of APP/PS1 transgenic mice. (a) nDNA and mtDNA were extracted from eight LAD and eight control subjects. We found levels of multiple oxidized bases were significantly higher in frontal, parietal, and temporal lobes and that mtDNA had approximately 10-fold higher levels of oxidized bases than nDNA. Eight-hydroxyguanine was approximately 10-fold higher than other oxidized base adducts in both LAD and control subjects. These results suggest that oxidative damage to mtDNA may contribute to the neurodegeneration of AD. (b) Mild Cognitive Impairment (MCI), the phase between normal aging and early dementia, is a common problem in the elderly with many subjects going on to develop AD. Results from eight amnestic MCI and six control subjects suggest oxidative damage to DNA occurs in the earliest detectable phase of AD. (c) Analysis of nDNA from the cortex of four groups (3m, 6m, 9m, 12m) of APP/PS1 and wild type mice showed elevations of 8-hydroxyguanine in 12 month old APP/PS1 mice.2) To analyze mitochondrial protein changes in LAD, 2D gels were run to separate proteins and MALDI-TOF mass spectrometry was used to identify proteins.Five mitochondrial proteins were significantly decreased in LAD. This proteomic study provides a proteome map of mitochondria in LAD brain and an insight into the pathogenesis of neuron degeneration in Alzheimer's disease.

Organic nitrates, such as glyceryl trinitrate (GTN), have been used clinically for more than a century. However optimal nitrate therapy is hindered by the development of tolerance, which is associated with a desensitized response to GTN, oxidative stress, and the inactivation of aldehyde dehydrogenase 2 (ALDH2). This thesis evaluated the ALDH2 inactivation hypothesis of GTN tolerance and investigated the role of oxidative stress in GTN tolerance mediated by the lipid peroxidation product, 4-hydroxynonenal (HNE). Evidence for a direct role of ALDH2 in nitrate action was sought using a stably transfected cell line that overexpressed ALDH2, or siRNA to deplete endogenous ALDH2. Neither manipulation altered GTN-induced cGMP formation, indicating that ALDH2 does not mediate GTN bioactivation and tolerance. In a second study using an in vivo GTN tolerance model and a cell culture model of nitrate action, a marked increase in HNE adduct formation was detected in GTN-tolerant tissues, and treatment with HNE reduced the cGMP and vasodilator responses to GTN, thus mimicking GTN-tolerance. Together, the results suggest a primary role for HNE in the development of GTN tolerance, and provide the framework for a unified hypothesis that accommodates the previous findings of sulfhydryl depletion, ALDH2 inactivation and oxidative stress that are associated with nitrate tolerance. Studies have implicated oxidative stress and increased HNE formation in the pathogenesis of Alzheimer’s disease (AD). It was hypothesized that the gene deletion of ALDH2 would result in increased HNE-adduct formation leading to impaired cognitive function, and AD-like pathological changes. We observed a marked increase in HNE-adduct formation in Aldh2-/- mouse hippocampi as well as hyperphosphorylated tau, activated caspases, age-related changes in hippocampal amyloid βeta1-42 (Aβ1-42), post-synaptic density protein 95 (PSD95) and phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB) expression, endothelial dysfunction and other vascular pathologies. These data provide further evidence for the importance of HNE and oxidative stress in AD pathogenesis, and establish Aldh2-/- mice as a new, oxidative stress-based animal model of age-related cognitive impairment and AD. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-05-31 11:10:58.145

One of the earliest symptoms of Alzheimer’s Disease (AD) is a loss of spatial navigation. In this work, we improved an existing screening test for AD that analyzed a patient’s spatial navigation ability. The existing screening test was made more immersive, and therefore more reliable, by integrating support for a leading-edge consumer-targeted Head-Mounted Display (HMD). This integration brought some technical and usability challenges, that were addressed. Furthermore, we investigated the rehabilitative potential of Virtual Reality Navigational (VRN) activities in two case studies: an Early Stage AD (ESA) participant and a Late Stage AD (LSA) participant. We found that the ESA participant was able to significantly improve his navigation skills, and we observed some qualitative improvements in memory and navigation in his personal life. The LSA participant did not improve noticeably at the VRN tasks, but his mood improved after participating in the treatment sessions. These case studies suggested that VRN treatment may be beneficial for people with AD, especially at the onset stage. / February 2017

According to research applying a social constructionist perspective, the sense of self is not lost in people with Alzheimer’s disease (AD). It is, however, greatly influenced by the symptoms and by how they are treated by other people. Without support, it is difficult to preserve a positive sense of self, when living with progressing cognitive impairments. The stigma associated with cognitive impairment also threatens their sense of self. Harré’s social constructionist theories of self and positioning have been used to study how people with AD express their sense of self. As there is a need to expand the previous research by involving additional participants and research contexts, the aim of the present thesis was to describe, in accordance with Harré’s theories of self and positioning, how people with AD expressed their sense of self in personal interviews and in support groups with other people with AD. The research consists of four substudies (I–IV), and has a qualitative, descriptive, and theory-testing approach. Thirteen people with mild and moderate AD were included, 11 of whom had the early onset form of the disease. Two support groups were formed, led by facilitators who supported the communication and the participants’ expressions of self. Each group met 10 times during an eight-month period. Topics were not predetermined, and introduced by both facilitators and participants. Semistructured interviews were conducted before the groups started and after they ended. The interviews and support group conversations were audio-recoded and analysed with qualitative content analysis, guided by Harré’s theories. In substudy I, the initial interviews were deductively analysed. The findings showed that Self 1 (the sense of being a singular, embodied person) was expressed by the participants without difficulties. Self 2 (the perception of one’s personal attributes and life history) was expressed as feeling mainly the same person. While some abilities had been lost, other had been developed. Self 3 (the socially constructed self) was described as mostly supported, but sometimes threatened in interactions with other people (I). In substudy II, support group conversations were analysed abductively with respect to expressions of Self 2. It was found that participants expressed Self 2 in terms of agency and communion, and a lack of agency and communion (II).In substudy III, a secondary analysis of the data from substudy II was performed inductively with the aim of describing how Self 3 was constructed in the interaction of the support group. Five first-order positions, generating lively interaction, were described: the project manager, the storyteller, the moral agent, the person burdened with AD, and the coping person (III). In substudy IV, all the collected data were reanalysed inductively, focusing on how participants expressed the experience of being research participants. Three themes were constructed: contributing to an important cause, gaining from participating, and experiencing risks and drawbacks (IV). In conclusion, it was found that participants constructed positive social selves through the support from each other, the facilitator, and researchers in the support group (III), and as research participants (IV). Agency and communion were central to Self 2, and decreased with the progression of AD (II). In spite of change, participants perceived themselves as basically the same people, with a potential to learn and develop as persons (I).

No description available.

Bakgrund: Vid Alzheimers sjukdom försämras de kognitiva funktionerna vilket innebär svåra psykiska och sociala funktionsnedsättningar. Det finns inget botemedel för Alzheimers sjukdom och dess sjukdomsförlopp är långdraget med upp till 10–15 år och leder sedermera att personen avlider. I tidiga skeden av Alzheimers sjukdom riskerar anhöriga förbinda sig med orimliga åtaganden utan tanke på sjukdomens progression och det ökande vårdbehovet. Syfte: Syftet med denna studie var att beskriva upplevelsen av att vara anhörigvårdare till personer med Alzheimers sjukdom samt granska datainsamlingsmetoden i de valda artiklarna. Metod: Föreliggande studie var en beskrivande litteraturstudie med deskriptiv design som baserades på 12 artiklar med både kvalitativ och kvantitativ ansats. Materialet inhämtades genom sökningar i databasen PubMed. Huvudresultat: Resultatet visar att anhörigvårdare till personer med Alzheimers sjukdom upplever känslor av oro, stress, ångest, skam och skuldkänslor vid vårdandet av sin anhörige. Dessa känslor upplevs som värre i relation med att sjukdomen progredierar och det ökade omvårdnadsbehovet leder till att anhörigvårdare känner rädsla över att bli utbrända och ett förlorat hopp om framtiden. Motsatsen till detta är anhörigvårdare med ett förhållningssätt att varje dag var unik och därför accepterande sin nya roll i livet. Detta gav anhörigvårdare högre livskvalitet och upplevde därmed mindre nivåer av ångest i vardagen som resulterade i hopp om framtiden. Slutsats: Hur anhörigvårdaren upplever situationer som negativ eller positiv präglas av hur de hanterar och förhåller sig till situationer. Strategierna som används ger antingen ökad eller minskad stress och korrelerar med risken för att bli utbränd. / Background: Alzheimer's disease is impaired cognitive functions, which means severe mental and social disabilities. There is no cure for Alzheimer's disease and its course is up to 10-15 years and subsequently leads to the person dies. In the early stages of Alzheimer's disease relatives commit themselves with excessive commitments with no thoughts given to the disease's progression and the increasing need for care. Within the health care the health professionals sees the problems associated with being a family caregiver and the risk of them becoming burned out. Aim: The aim of this study was to describe the experience of being a family caregiver to people with Alzheimer’s disease and examine the data collection method in the selected articles. Method: The present study was a literature study with a descriptive design based on 12 scientific articles with both qualitative and quantitative approach. The material was gathered through searches in the database PubMed. Main results: The result shows that the family caregivers of people with Alzheimer's disease experience feelings of anxiety, stress, shame and guilt when caring for their loved one. These feelings are experienced as worse in relation with the disease progresses and the increased need for nursing leads to that the family caregivers feel fear of becoming burned out and feel lost hope for the future. The opposite of this is family caregivers with an attitude that every day was unique and therefore accepting their new role in life. This gave the family caregivers a higher quality of life and thus less experienced levels of anxiety in everyday life that resulted in feeling hope for the future. Conclusion: The experience of the family caregivers could either be positive or negative in managing of a person with Alzheiemer’s disease. The way of managing characterized how the family caregiver relates to situations. The managing of the strategys either reduce or induce levels of stress and correlates with the risk of being bournt-out.

Bakgrund: Alzheimers sjukdom (AS) kallas ofta för den anhöriges sjukdom med anledning av att sjukdomen även påverkar de närstående. Det är därför av vikt att sjuksköterskan arbetar utifrån ett helhetsperspektiv för att på så sätt få en förståelse för vilken inverkan AS har på familj och närstående. Syfte: Syftet med studien var att beskriva upplevelsen av hur livskvalitén påverkas av att vara närstående till en person med AS. Metod: En kvalitativ innehållsanalys, där självbiografiska verk har analyserats Resultat: Resultatet presenteras med tre kategorier ”En ny vardag”, ”Leva med ett lidande” och ”Ett tungt ansvar”. Varje kategori har två underkategorier vardera. . Det liv och den vardag som tidigare var känd för den närstående blev till ett minne. Nya utmaningar i vardagen och ett tungt ansvar väntade som resulterade att livskvalitén blev påverkad. Psykisk och fysisk ohälsa blev ett faktum. Slutsats: Det fanns flera faktorer till att livskvalitén blev försämrad. En faktor var att den närstående fick ta hela ansvaret för att vardagen skulle fungera i hemmet och spelade därför en viktig roll för personen med AS. Med anledning av detta måste sjuksköterskan kunna stödja den närstående så att denne orkar med sin vårdande roll och minimera risken för psykisk ohälsa. / Background: Alzheimer´s disease is often called the relative's illness on the grounds that the disease also affects the relatives. It is therefore important that the nurse working with a holistic approach and obtain an understanding of the impact of Alzheimer´s disease on family and relatives. Purpose: The purpose of this study is to describe the experience of how quality of life is affected by being related to a person with Alzheimer's disease. Method: This is an qualitative content analysis, where autobiographical works have been analyzed. Results: The results are presented in three categories: "A new day", "Living with suffering" and "A heavy responsibility." Each category has two subcategories. The life that was previously known to the relatives became a memory. New challenges in everyday life and a heavy responsibility that resulted in that the quality of life was affected. Mental and physical health became a fact. Conclusion: There were several factors that led to impaired quality of life. One factor was that the relatives had to take full responsibility for everyday life and played an important role for the person with Alzheimer´s disease. For this reason, the nurse must be able to support the relatives so that they can cope with their caring role and minimize the risk of mental illness.

The aim of the research presented in this thesis was to improve the characterisation of the changes in brain structure and function that occur at different stages of Alzheimer’s disease (AD) progression, from pre-symptomatic AD, to mild cognitive impairment (MCI), to clinically evident dementia, using magnetic resonance imaging (MRI) techniques. Baseline structural MRI data from a cohort of healthy older adults who were followed prospectively for ten years, during which time some developed MCI and some AD, were analysed. It was found that structural MRI could detect volume loss in medial-temporal lobes up to 7-10 years before clinical symptoms of AD appear. In addition, volumetric variability of medial-temporal regions detected by structural MRI across cognitively healthy older adults correlated with their performance on a task of visuospatial associative memory, and functional activation of the same regions occurred during successful performance of the same task on functional MRI (fMRI). Three groups of participants - cognitively healthy controls, people with MCI, and patients with probable AD - were then recruited and underwent a multimodal MRI protocol, which included functional sequences acquired at rest and during the execution of two different cognitive tasks (visuospatial associative memory and self-appraisal). Cross-sectional comparisons showed: (i) that successful visuospatial associative memory performance was associated with increased functional activity (measured with task fMRI) in lateral prefrontal regions in AD patients relative to controls and (ii) that increased functional activity overlapped with frontal brain networks showing increased functional connectivity (measured with resting fMRI) in the same AD patients. Further, by demonstrating group- and condition-specific decreased frontal activity in AD patients relative to controls during a self-appraisal fMRI task, it was shown the specific utility of fMRI to unravel cognitive mechanisms underlying specific neuropsychological symptoms such as unawareness of cognitive impairment (anosognosia) in MCI and AD. In conclusion, structural MRI can detect morphological changes in the preclinical stage of AD, possibly earlier than previously described, and these reliably match cognitive functioning in older adults. In the MCI and AD stages, once symptoms of cognitive impairment are clinically evident and measurable, task-related and resting functional MRI can inform on residual brain function detectable over and above the known changes in brain morphology and cognitive performance that have already occurred at these stages, emerging as a sensitive marker of residual ability that could potentially be used to measure the effect of new treatments.