Nuclear factor kappa B (NF-κB) mediated signalling is complex and plays a critical role in many biological processes. Investigators have reported that NF-κB is activated during the induction of long term potentiation (LTP), a proposed mechanism for memory encoding, and may be a requirement for synaptic plasticity and memory. In this study, mRNA extracted from hippocampal slices of NF-kB p50 knockout mice and its littermate before and after induction of LTP was analyzed using DNA microarray analysis (Affy-metrix GeneChip® Mouse Genome 430 2.0) to explore candidate target genes of NF-kB in LTP. The early growth response 2 (Egr-2) was identified as one putative NF-kB target gene. Egr-2 mRNA and protein analysis of primary cortical neurons and HeLa cells chemically stimulated with Tumor Necrosis Factor α (TNFα) to activate the NF-kB sig-nalling pathway confirmed the microarray results. In addition, examination of the Egr-2 promoter sequence for NF-kB binding sites using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) confirmed promoter occupancy and specificity of binding in vivo, respectively. These data suggest that Egr-2 expression level is controlled by direct transcriptional activity of the NF-kB transcription factor.

There is an absence of nursing studies that explore interventions to enhance psychological well-being for advanced Alzheimer patients. While sensory stimulation has been identified as a nursing intervention for dementia patients. Few studies reporting the effects of such interventions for patients with late stage dementia are available. The purpose of this study was to examine the effects of sensory stimulation activities on the psychological wellbeing of advanced Alzheimer patients. The conceptual model of “the good life” developed by Lawton (1983) provided the framework for this study. A descriptive design with a single group and pre-test post-test repeated measures analysis of variance was used for this study.A convenience sample of 15 patients from three Midwest long-term care facilities was observed for the effects of music. Touch and smell on psychological well-being as measured by the Discomfort Scale for Dementias of the Alzheimer Type (DS-DAT) (Hurley, Volicer, Hanrahan, Houde & Volicer, 1992). The rights of patients were protected at all times, with legal guardians receiving a written explanation of the study. Actual stimulation activities were conducted by Activity Directors or assistants from each facility.Paired t-test analysis of data revealed that DS-DAT scores for all three stimulation activities were significantly lower at <.05 level of significance than baseline DS-DAT scores. Lower DS-DAT scores included more positive affect behaviors and fewer negative affect behavior. A conclusion was drawn that the three sensory stimulation activities increased psychological well-being in the advanced Alzheimer patient sample. This study was significant because findings will support rationale for education of nursing staff in sensory stimulation procedures and provide information on evaluation of intervention outcomes for advanced Alzheimer patients. / School of Nursing

Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / Department of Educational Psychology

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.

Nuclear factor kappa B (NF-κB) mediated signalling is complex and plays a critical role in many biological processes. Investigators have reported that NF-κB is activated during the induction of long term potentiation (LTP), a proposed mechanism for memory encoding, and may be a requirement for synaptic plasticity and memory. In this study, mRNA extracted from hippocampal slices of NF-kB p50 knockout mice and its littermate before and after induction of LTP was analyzed using DNA microarray analysis (Affy-metrix GeneChip® Mouse Genome 430 2.0) to explore candidate target genes of NF-kB in LTP. The early growth response 2 (Egr-2) was identified as one putative NF-kB target gene. Egr-2 mRNA and protein analysis of primary cortical neurons and HeLa cells chemically stimulated with Tumor Necrosis Factor α (TNFα) to activate the NF-kB sig-nalling pathway confirmed the microarray results. In addition, examination of the Egr-2 promoter sequence for NF-kB binding sites using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) confirmed promoter occupancy and specificity of binding in vivo, respectively. These data suggest that Egr-2 expression level is controlled by direct transcriptional activity of the NF-kB transcription factor.

The amyloid-β precursor protein (APP) has been widely studied due to its role in Alzheimer´s disease (AD). When APP is sequentially cleaved by β- and γ-secretase, amyloid-β (Aβ) is formed. Aβ is prone to aggregate and is toxic to neurons. However, the main processing pathway for APP involves initial cleavage at the α-site, within the Aβ region, instead generating a neuroprotective soluble fragment, sAPPα. APP is a member of a protein family, also including the proteins APLP1 and APLP2, which are processed in a similar way as APP. In addition, K/O studies in mice have shown that the three proteins have overlapping functions where APLP2 play a key physiological role. The aim of this thesis was to study mechanisms underlying the α-secretase processing of APP and APLP2. We have used the human neuroblastoma cell-line SH-SY5Y as a model system and stimulated α-secretase processing with insulin-like growth factor-1 (IGF-1) or retinoic acid (RA). Our results show that the stimulated α-site cleavage of APP and APLP2 is regulated by different signaling pathways and that the cleavage is mediated by different enzymes. APP was shown to be cleaved by ADAM10 in a PI3K-dependent manner, whereas APLP2 was cleaved by TACE in a PKC-dependent manner. We further show that protein levels and maturation of ADAM10 and TACE is increased in response to RA, mediated by a PI3K- or PKC-dependent signaling pathway, respectively. Another focus of our research has been O-GlcNAcylation, a dynamic post-translational modification regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase (OGA). We show that decreased OGA activity stimulates sAPPα secretion, without affecting APLP2 processing. We further show that ADAM10 is O-GlcNAcylated. Lastly, we show that APP can be manipulated to be cleaved in a similar way as APLP2 during IGF-1 stimulation by substituting the E1 domain in APP with the E1 domain in APLP2. Together our results show distinct α-site processing mechanisms of APP and APLP2. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 4: Manuscript; Paper 5: Manuscript.</p>

No description available.

Subcortical hyperintensities (SH) are believed to be observable signs of cerebrovascular disease, indicating some form of subcortical vasculopathy. Also commonly referred to as leukoariosis, these hyperintense signals on proton density, T2-weighted and fluid attenuated inversion recovery magnetic resonance images, are commonly observed phenomena in Alzheimer’s disease patients and elderly persons. Several SH sub-types with differential brain-behavior associations have been proposed in the scientific literature: periventricular, deep white, cystic fluid filled lacunar-like infarcts and perivascular Virchow-Robin spaces. This study will present Lesion Explorer (LE): a comprehensive tri-feature MRI-based processing pipeline that effectively and reliably quantifies SH sub-types in the context of additional brain tissues volumetrics in a regionalized manner. The LE pipeline was validated using a scan-rescan procedure. Finally, the LE pipeline was applied in a cross-sectional study of Alzheimer’s disease patients and normal elderly controls. Brain-behavior relationships were demonstrated with regional SH volumes and executive functioning, speed of mental processing, and verbal memory.

Alzheimer’s disease (AD), a progressive age-related neurodegenerative disorder is characterized by impairments in memory and cognitive functions. The two main pathogenic hallmarks associated with the progression of this multifactorial disease include accumulation of amyloid-beta (Aβ) plaques and the deterioration of the cholinergic system in the brain. Using cost-effective synthetic procedures, mono-, di-, and tri- substituted sym-triazine derivatives incorporating acetylcholine substrate analogues and aromatic phenyl moieties were synthesized for the targeted modulation of Aβ aggregation and acetylcholinesterase (AChE) activity. A subset of these sym-triazines demonstrated dual inhibition of Aβ fibrillization and AChE hydrolytic activity in vitro studies. These highly effective compounds were also shown to be well tolerated by differentiated human neuronal cells in cell viability tests. These novel compounds have the potential to undergo future in vivo pharmaceutical analysis and have a positive impact on the quality of life of the people living with this devastating disease and their caretakers.

The presence of white matter hyperintensities (WMH) and silent infarcts on magnetic resonance imaging is a common finding in elderly individuals. This subcortical ischemic vasculopathy is associated with age and cerebrovascular risk factors and can increase the risk of dementia, yet the contribution of subcortical vascular disease to the clinical profile and progression of Alzheimer’s disease patients is still relatively poorly understood. This study assessed the presence, severity and progression of WMH and lacunar infarcts and studied their relationship with measures of brain function and cognition in 64 patients with Alzheimer’s disease. Both a visual rating scale and volumetric tissue segmentation analysis were used to evaluate brain-behaviour relationships of WMH seen on T2-weighted and Proton Density MRI scans. In addition to describing the topographical distribution of WMH and lacunes, and examining sex differences, the volume and location of WMH were correlated with executive function, frontal lobe perfusion, and medial temporal lobe atrophy. The results confirm and extend previous findings suggesting that WMH are located primarily in the frontal and parietal regions and are associated with mild decline in tasks of executive function. WMH severity was not associated with a decrease in frontal lobe perfusion as measured by Single Photon Emission Computed Tomography. The investigation of different WMH subtypes revealed that lacunar infarcts were found most often within deep WMH. At one year follow-up, progression was seen in deep WMH, specifically in the frontal lobe and in lacunes found within the periventricular regions. Furthermore, progression in WMH was associated with a decline in cognition. Taken together, these studies indicate the utility of measuring WMH by subtype (periventricular and deep WMH and lacunes) in understanding progression patterns and brain-behavior relationships. Since, subcortical ischemic vasculopathy may be potentially preventable; this study underlines the need to study interventions that address risk factors for the development of small vessel cerebrovascular disease, which may be helpful in preventing disability in the elderly.