Alzheimer's disease (AD) is a condition marked by progressive intellectual decline and memory loss, which typically affects individuals over the age of 60. Its origins are unknown but genetic factors are suspected in some cases. There is limited information about the subjective experience of AD although it is often described as a calamity that inevitably destroys the self irrespective of its victims' social circumstances. This dissertation offers an alternative to this nihilistic portrayal that draws on a critical phenomenological framework. It explores the loss of self as an intersubjective phenomenon that is mediated by three contexts: (1) Western representations of the self as autonomous and individualistic; (2) the public description of AD; and (3) the biomedical practices that construct AD as a diagnostic object. / The dissertation examines the experiences of 16 patients and 37 family members who participated in a multi-disciplinary assessment at a dementia clinic. The participants also include 14 clinicians and staff members from the clinic. The findings are derived from a prospective study that includes in-depth, at-home interviews and observations of clinical assessment activities and research-based genetic counseling. The dissertation examines how memory trouble interferes with the intersubjective fabric of everyday life in families as affected participants lose the ability to meaningfully reciprocate on the basis of their individualistic identities. The analysis emphasizes the role of the clinical assessment, diagnosis, and public description in restoring intersubjective order. A salient aspect of this process is the way in which medicalized interpretations of memory trouble facilitate reinterpretation of the eroding self as being animated by pathology. The self is thus rendered meaningful again as it is being indexed to lay descriptions of what people do and say in AD. The analysis also considers how this process extends to participants who came to perceive themselves as victims of AD although they were assessed as not having a dementia disorder. The dissertation finally considers the impact of acquiring genetic knowledge about AD on interpretations of the self. Overall, the research underscores the loss of self in AD as a phenomenological process that is mediated by familial and institutional contexts.

Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Individuals with DS exhibit a very early onset of AD neuropathology, byt heir mid to late 30's. Extra copies of the genes on chromosome 21 may play an important role in this accelerated onset of AD in DS individuals. The amyloid precursor protein (APP) is located on chromosome 21, and among its cleavage products is amyloid-beta (Aß), a component of amyloid plaques. The presence of Aß and amyloid in the brain is a key pathogenic factor, and is considered the central and causative neuropathology in AD by the amyloid cascade hypothesis. Growing evidence suggests an important role for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromsome 21, and is believed to participate in the maintenance of cholesterol homeostasis. The effects of ABCG1 expression on the production of Aß have proved inconclusive in in vitro studies, demanding an in vivo resolution where appropriate physiology is maintained. To test the hypothesis that overexpression of ABCG1 will accelerate the onset or progression of AD in vivo, we evaluated the cognitive performance of ABCG1-overexpressing mice before and after crossing to the PDAPP mouse model of AD. Both normal and AD mice overexpressing ABCG1 showed no significant deficits on several cognitive tests, including reference and working memory task variations of the Morris Water Maze. Golgi analysis of neuronal structure revealed significantly reduced dendritic complexity in both normal and PDAPP mice overexpressing ABCG1, suggesting that the cholesterol-related functions of ABCG1 have a potentially important role in dendrite development. Interestingly, behavioural analysis of ABCG1-deficient mice revealed a gene-dose dependent trend toward worsened performance on the water maze probe trial, suggesting that the pathways that may compensate for ABCG1 overexpression could be unable to offset a complete deficiency. These experiments suggest an important role for ABCG1 in maintaining cellular cholesterol homeostasis, but do not support the hypothesis that ABCG 1 expression contributes to the accelerated onset of AD pathology in DS individuals.

ApoE is a polymorphic protein that has been found to play many different roles in biological processes including lipid transport, neurobiology and immunoregulation. ApoE occurs in the human population in three major isoforms; apoE2, apoE3 and apoE4. The apoE4 isoform has been identified as a major risk factor for several diseases including atherosclerosis and Alzheimer's disease, therefore a greater understanding of apoE biology is highly sought after. In my thesis, I have investigated several novel aspects of apoE biology. I have identified an association between increased apoE expression and apoptosis in a neuronal cell type and demonstrated that apoE becomes enriched within the neuronal apoptotic debris, consistent with a possible role for apoE in facilitating apoptotic debris clearance. A possible anti-apoptotic role of apoE in macrophages was assessed by reducing or eliminating apoE expression using siRNA and cells isolated from apoE knockout animals, respectively. The removal of apoE did not alter overall sensitivity to apoptosis, however, it did significantly increase staurosporine-induced caspase-3 activation. In other studies, the poorly understood accumulation of apoE within the nucleus was found to be enhanced during serum starvation and to localise in intra-nuclear structures that are distinct from inter-chromatin granule clusters. Analysis of apoE within the human brain revealed a correlation between fragmentation and the apoE3 isoform which was independent from AD status and brain region examined. Additionally, a portion of brain apoE3 was found to be present in the form of disulphide-linked dimers. Collectively, these studies have further expanded the current knowledge of apoE biology in terms of its association with apoptosis, nuclear localization and structural differences between the apoE3 and apoE4 isoforms in the human brain.

Alzheimer??s disease (AD) is the most common form of dementia affecting the elderly. Extracellular deposition of beta amyloid (Abeta plaques), intraneuronal tau accumulation, inflammation (activated astrocytes and microglia), and neuronal loss are all consistent pathological features of the disease. Unlike Abeta plaques, inflammation correlates with neuronal loss and cognitive decline in AD, suggesting it plays an important role in disease progression. Recent research has also identified soluble oligomeric Abeta species in the AD brain, which correlate with disease progression and are proposed to be more neurotoxic than their fibrillar counterpart. The main aims of this thesis were to determine whether oligomeric Abeta is a more powerful stimulator of the inflammatory response compared to fibrillar forms of the protein, to identify potential mediators of this response and to determine downstream neuronal changes. Isolated human primary astrocytic, microglial and neuronal cell cultures were used to assess which Abeta alloform and conformation was more neurotoxic and neuroinflammatory. A total of 17 inflammatory cytokines and chemokines were measured simultaneously using a Multiplex approach and neurotoxicity was assessed by lactate dehydrogenase release. Cell cultures involving all three cell types were also used to examine these inflammatory mediators in a more complex system, and direct changes in tau levels and/or phosphorylation determined by western immunoblotting. Further immunohistochemical analysis determined the localisation of oligomeric Abeta within post-mortem human AD brain tissue. The data clearly shows that oligomeric Abeta was more neurotoxic and neuroinflammatory than fibrillar Abeta, with oligomeric Abeta40 favoured in toxic plaque deposits in AD brain tissue. Cell culture experiments showed that glia clearly mediate neuroprotection against oligomeric Abeta. Soluble TNF-alpha, IL-2, IL-4 and IL-12 mediate this response early in disease, with a decline in their secretion and a sustained increase in IL-1alpha, IFN-gamma, GM-CSF, MIP-1beta, and IL-8 provoking increased tau protein expression. Overall, the data clearly demonstrates oligomeric Abeta more powerfully stimulates a suite of inflammatory mediators affecting neuronal survival and tau pathology, although the contribution of additional glial-derived factors must also be determined. The identification of these inflammatory mediators, in combination with other potential factors, may lead to the development of mechanistic therapeutic interventions that could target these early pathological changes.

Alzheimer??s disease (AD) is the most common form of dementia affecting the elderly. Extracellular deposition of beta amyloid (Abeta plaques), intraneuronal tau accumulation, inflammation (activated astrocytes and microglia), and neuronal loss are all consistent pathological features of the disease. Unlike Abeta plaques, inflammation correlates with neuronal loss and cognitive decline in AD, suggesting it plays an important role in disease progression. Recent research has also identified soluble oligomeric Abeta species in the AD brain, which correlate with disease progression and are proposed to be more neurotoxic than their fibrillar counterpart. The main aims of this thesis were to determine whether oligomeric Abeta is a more powerful stimulator of the inflammatory response compared to fibrillar forms of the protein, to identify potential mediators of this response and to determine downstream neuronal changes. Isolated human primary astrocytic, microglial and neuronal cell cultures were used to assess which Abeta alloform and conformation was more neurotoxic and neuroinflammatory. A total of 17 inflammatory cytokines and chemokines were measured simultaneously using a Multiplex approach and neurotoxicity was assessed by lactate dehydrogenase release. Cell cultures involving all three cell types were also used to examine these inflammatory mediators in a more complex system, and direct changes in tau levels and/or phosphorylation determined by western immunoblotting. Further immunohistochemical analysis determined the localisation of oligomeric Abeta within post-mortem human AD brain tissue. The data clearly shows that oligomeric Abeta was more neurotoxic and neuroinflammatory than fibrillar Abeta, with oligomeric Abeta40 favoured in toxic plaque deposits in AD brain tissue. Cell culture experiments showed that glia clearly mediate neuroprotection against oligomeric Abeta. Soluble TNF-alpha, IL-2, IL-4 and IL-12 mediate this response early in disease, with a decline in their secretion and a sustained increase in IL-1alpha, IFN-gamma, GM-CSF, MIP-1beta, and IL-8 provoking increased tau protein expression. Overall, the data clearly demonstrates oligomeric Abeta more powerfully stimulates a suite of inflammatory mediators affecting neuronal survival and tau pathology, although the contribution of additional glial-derived factors must also be determined. The identification of these inflammatory mediators, in combination with other potential factors, may lead to the development of mechanistic therapeutic interventions that could target these early pathological changes.

Thesis (Ph. D.)--University of Washington, 1992. / Vita. Includes bibliographical references (leaves [134]-150).

Thesis (D. Min.)--Ashland Theological Seminary, 2007. / Abstract. Includes portions of the devotional manual, In the midst. Includes bibliographical references (leaves 213-223).

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Additional advisors: Paul D. Blanton, David G. Clark, Roy C. Martin, Virginia G. Wadley. Description based on contents viewed Feb. 9, 2009; title from PDF t.p. Includes bibliographical references (p. 63-76).

Thesis (D. Min.)--Ashland Theological Seminary, 2007. / Abstract. Includes portions of the devotional manual, In the midst. Includes bibliographical references (leaves 213-223).

Thesis (M.S. in psychology)--Washington State University, December 2008. / Title from PDF title page (viewed on Feb. 19, 2009). "Department of Psychology." Includes bibliographical references (p. 28-32).