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.

Neuroinflammation occurs in Alzheimer’s disease (AD) brain, and plays a role in neurodegeneration. The main aim of this study was to determine how treatments with exogenous apolipoprotein E (ApoE2, E3 and E4 isoforms), a genetic risk factor for AD, affects the amyloid-β (Aβ) induced inflammatory response in vitro in astrocytes. Recombinant, lipid-free ApoE4 was found not to affect Aβ-induced inflammation in rat astrocytes, while ApoE2 showed a protective effect. Mouse cells expressing human ApoE isoforms, which have similar lipidation and modification to native human ApoE, showed ApoE4 promoting inflammation, and no ApoE2 protective effect upon Aβ treatment. A Protein/DNA array was used to screen 345 transcription factors in rat astrocytes treated with Aβ and/or ApoE isoforms, in order to determine which contribute to the observed ApoE2 protection. Some candidates were validated by Western Blot or EMSA and/or by inhibition or activation. The findings suggest ApoE isoforms differentially regulate Aβ-induced inflammation, and multiple signalling pathways are involved in the process.

The purpose of this study was to determine if distinct subgroups of patients with Senile Dementia of the Alzheimer Type (SDAT) could be identified using seven scales of the Cognitive Behavior Rating Scale (CBRS). Ward's method of cluster analysis was used to group 104 patients with a probable diagnosis of SDAT into subtypes.The following three clusters were identified: (a) Moderately Impaired, (b) Severely Impaired, and (c) Emotionally Intact which displayed differences in symptom severity. Clusters could be partially defined by the amount of time they had been diagnosed with the disease. Differences in the cluster's configuration of scores had little/no descriptive utility. Subsequent discrimination analyses indicated that patient demographics were not as useful as the CBRS in classification of patients.This study provided evidence for the CBRS's ability to differentially portray SDAT patients' profiles. Results provide partial support for a stage model of SDAT. Implications of existing subgroups in SDAT are discussed as they pertain to patient management issues. / Department of Counseling Psychology and Guidance Services

Neuroinflammation occurs in Alzheimer’s disease (AD) brain, and plays a role in neurodegeneration. The main aim of this study was to determine how treatments with exogenous apolipoprotein E (ApoE2, E3 and E4 isoforms), a genetic risk factor for AD, affects the amyloid-β (Aβ) induced inflammatory response in vitro in astrocytes. Recombinant, lipid-free ApoE4 was found not to affect Aβ-induced inflammation in rat astrocytes, while ApoE2 showed a protective effect. Mouse cells expressing human ApoE isoforms, which have similar lipidation and modification to native human ApoE, showed ApoE4 promoting inflammation, and no ApoE2 protective effect upon Aβ treatment. A Protein/DNA array was used to screen 345 transcription factors in rat astrocytes treated with Aβ and/or ApoE isoforms, in order to determine which contribute to the observed ApoE2 protection. Some candidates were validated by Western Blot or EMSA and/or by inhibition or activation. The findings suggest ApoE isoforms differentially regulate Aβ-induced inflammation, and multiple signalling pathways are involved in the process.

Thesis (M.S.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains ix, 76 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 71-76).

Thesis (M.S.)--George Mason University, 2008. / Vita: p. 48. Thesis director: Dmitri Klimov. Submitted in partial fulfillment of the requirements for the degree of Master of Science in Bioinformatics and Computational Biology. Title from PDF t.p. (viewed Mar. 17, 2009). Includes bibliographical references (p. 45-47). Also issued in print.

Thesis (M.A.) - Carleton University, 2002. / Includes bibliographical references (p. 56-64). Also available in electronic format on the Internet.