Thesis (M.A.)--Eastern Illinois University, 1998. / Includes bibliographical references (leaves 42-45).

Thesis (Ph. D.)--Ohio State University, 2004. / Document formatted into pages; contains 241 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 July 27.

Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 248-272). Available also in a digital version from Dissertation Abstracts.

Alzheimer’s disease is the most common cause of late-life dementia and the fourth leading cause of death in the developed world. The aetiology of AD has not yet been resolved. It has been suggested that AD could result from multifactorial process involving both a genetic predisposition and an exposure to environmental factors modulated by the biological aging process. To date, epidemiological and molecular genetic data have led to the identification of three genes, amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes, which, when mutated, can cause an early onset form of AD. Genetic linkage studies and association studies have also shown that the ε4 allele of the apolipoprotein E gene increases risk for AD in a dose dependent manner in both early onset and late onset AD. Recently, it has also been suggested that environmental factors may interact with a genetic predisposition to modify the risk of AD. Extensive research is underway to identify environmental and genetic risk factors for this complex disease. Over 40 genes have been tested as AD candidates yet none has been clearly established as an AD risk factor. Currently scientists are investigating the interrelationship between various gene loci and how environmental factors could affect an individual’s susceptibility to AD. This study evaluated the genotoxicity of environmental agents such as hydrogen peroxide, cadmium chloride and γ radiation induced oxidative DNA damage in lymphocytes and within specific DNA sequences of APP (exon 15-18) and PS1 (exon 3-12) genes of AD patients and age-matched control subjects. As indicators of oxidative DNA damage, the frequencies of DNA strand breaks, oxidized pyrimidines and altered purines was assessed using the alkaline Comet assay modified with lesion-specific endonucleases, endo-III and fpg; and fluorescence in situ hybridisation. The number of APP and PS1 hybridisation spots per comet were used as an indicator of the extent of damage. The location of the hybridisation spots in the head or tail of the comet were recorded to further determine whether the gene of interest lies within or in the vicinity of a damaged region of DNA. With the alkaline Comet assay modified with endo-III and fpg, it was demonstrated that patients with AD had significantly increased levels of DNA strand breaks, oxidized pyrimidines and altered purines induced by hydrogen peroxide, cadmium chloride and γ radiation compared with control subjects (p<0.05). This was further confirmed by the fluorescence in situ hybridisation modification of the alkaline Comet assay by demonstrating a significant increase in the mean number of APP and PS1 gene hybridisation spots per comet in AD patients compared with control subjects. Moreover, the gene sensitivity index of APP and PS1 to hydrogen peroxide, cadmium chloride and γ radiation were found to be higher in AD patients than in control subjects. Taken together, our results suggest (i) that lymphocytes from patients with AD are sensitive to these environmental genotoxic agents and (ii) there was an overall increase in the mean number and sensitivity index of APP and PS1 genes to environmental genotoxic agents which might link a genetic cause to oxidative stress in peripheral cells of AD patients than in control subjects. Although the mechanisms by which these environmental agents induced oxidative DNA damage remained to be elucidated, our data suggest that increased oxidative stress is an inherent property of cells carrying genes associated with AD. / Dr. H. Abrahamse Mrs. J. V. Hind

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Thesis (Ph. D.)--University of Washington, 1990. / Vita. Includes bibliographical references (leaves [221]-239).

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: SHSY, LDH, Ependymin, Alzheimer's. Includes bibliographical references (leaves 34-38 ).

Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disease. The candidate aetiological agent for this disease is the 4kDa amyloid beta (Ab) peptide which is derived from the proteolytic cleavage of the amyloid precursor protein (APP) by the b- and g- secretase, respectively. As cellular prion proteins (PrPc) both regulate the cleavage of APP and mediate Ab induced neurotoxicity, a study was undertaken to establish whether the cellular receptor for PrPc, namely the 37kDa/67kDa laminin receptor (LRP/LR) also played a role in AD pathology. Anti LRP/LR specific antibody (IgG1-iS18) blocking LRP/LR resulted in a significant reduction of both Ab and sAPPb levels (the cleavage products of b-secretase), while APP, b- and g-secretase cell surface levels remained unaltered. LRP/LR was found to co-localise with APP, b- and g-secretase both on the cell surface and intracellularly. Furthermore, FRET demonstrated that an interaction existed between presenilin 1 (PS1) of the g-secretase and LRP/LR, while co-immunoprecipitation confirmed that LRP/LR interacted with both b-secretase and PS1. These results indicate that LRP/LR is implicated in the amyloidogenic processing of APP, through an indirect interaction with the b-secretase and a direct interaction with the g-secretase. These findings also suggest the possibility of utilising IgG1-iS18 as a possible therapeutic for the treatment of AD.

This study aims to discover whether there is a correlation between atypical clinical presentations of Alzheimer’s disease (AD) and atypical distribution patterns of AD pathology. To provide a measure of the atypical clinical presentations, we obtained standardized neuropsychological test scores for a group of 345 subjects of the Boston University Alzheimer’s Disease Center cohort that had received a clinical or pathological diagnosis of AD. Each of the neuropsychological test scores included in our analyses was classified into one of five cognitive domains, according to the primary domain each test assesses: memory, executive function, attention, visuospatial function, and language. From these test scores, global cognitive performance scores and individual domain performance scores were calculated for a subset of 53 subjects that had brain tissue slides available for pathological analysis. Difference scores were computed for each domain, providing a within-subject comparison of performance between each individual cognitive domain and overall cognitive performance. For these same 53 subjects, tissue slides from six brain regions were obtained and digitally scanned. Neurofibrillary tangle (NFT) quantification was performed for all tissue slides using a computer algorithm modified to recognize AT8 staining patterns. NFT densities were then calculated for five general brain regions (frontal, parietal, temporal, limbic and occipital). In addition, a global NFT density score was computed for each subject, averaging NFT densities across all regions. From these densities, difference scores were calculated for each brain region individually, providing a measure of how each region’s NFT density compares to the overall brain NFT density. Multiple linear regressions analyses were performed with five pairs of cognitive domain difference scores and region NFT density difference scores: memory difference scores and limbic difference scores, executive function difference scores and frontal difference scores, attention difference scores and parietal difference scores, visuospatial difference scores and occipital difference scores, and language difference scores and occipital difference scores. Though we expected to observe significant negative correlations between each of the five difference score pairs, the only statistically significant correlation observed was between memory difference scores and limbic difference scores (β= -0.361, p<0.05). These results suggest that poorer performance in memory-related neuropsychological tests, when compared to global cognitive performance, can predict higher NFT densities in limbic regions when compared to the overall brain pathology. Although no other difference score pairs showed any statistically significant correlations, many study limitations, including small sample size and simplifications in analysis, should be addressed in the future to provide better understanding of these atypical presentations of AD and their underlying pathologies.