The first focus of this thesis was to determine whether motor learning and recognition memory was intact in Line 66+/+ mice, a mouse model which mimics neurodegenerative disease coupled with tau aggregation. Line 66+/+ display positive tau pathology in forebrain, hindbrain and spinal cord by 5 weeks of age. At 4 months of age Line 66+/+ mice were impaired in the motor learning task suggesting that tau pathology had decreased motor performance. Treatment with an anti tau aggregating drug reversed motor learning deficits in Line 66+/+ mice. At 5 months of age Line 66+/+ mice exhibited deficits in the social recognition. This result indicates that transgenic influences on Line 66+/+ mouse performance had extended to social memory function. The second focus of this thesis was investigating recognition memory of a novel triple transgenic model of AD, the PLB1 mouse model. Generation of the PLB1 mouse model came from the realisation that many of current mouse models for AD display major disadvantages in the fact that there is no control for the disturbance caused by the insertion of the transgene(s) with many of them lacking age-specificity, as well as brain-region and cell-type specificity. PLB1Double mice were generated using a knock-in procedure for integration of a single construct containing mutated APP and tau under the control of a forebrain- and age-specific CaMKII promoter. PLB1Double mice were crossed with a PSEN expressing mouse line generating the PLB1Triple line. APP and tau transgenes were flanked by floxed and flirted allowing direct comparison between animals containing one, two or three AD-relevant transgenes. PLB1Triple mice exhibit neuropathological changes by 6 months of age. PLB1mice displayed deficits in behavioural paradigms from 8 months of age suggesting that transgene inclusion had affected recognition of spatial, object and social information.

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No description available.

Alzheimer’s disease (AD) is a dementia that unfortunately affects many people around the world and also here in Manitoba. This practicum explores how an interactive environment can potentially improve the quality of life for people living with AD. The learning objectives of this project were to investigate how an environment designed with total wellness in mind can support residents with AD. Specifically, the residents are millennials – people born in the 1980s to 2000s. The environment is one floor of a personal care home. An extensive literature review was conducted of topics relating to wellness, mental, physical, and spiritual health. The role of community and socialization’s effect on quality of life was researched. Precedents were also analyzed. These investigations, along with programming led to a design which provides a therapeutic central hub for residents to visit and socialize with others while enjoying a variety of activities, both planned and spontaneous. / October 2016

The Amyloid Cascade Hypothesis states that fibrillation of the amyloid beta (Aβ) peptide is the primary cause of Alzheimer’s pathology. The trigger for the fibrillation is a subject of much debate, although it is clear, oxidative stress is a key feature of Alzheimer’s aetiology. This thesis explores a possible role of oxidation of Aβ, in particular the effect of histidine and methionine side-chain oxidation, on Aβ fibril growth rates. Within chapters 2 and 3 of this thesis is a discussion of various approaches to chemical synthesis of 2-oxo-histidine with a view to the incorporation of the oxidised amino acids into Aβ peptide using Fmoc approaches. Chapter 2 describes attempted chemical transformation of (protected) L-histidine into L-oxohistidine. Dimethyldioxirane oxidised Boc-His-OMe yielded products containing isopropylidene groups, while oxidation using a Cu(II)/ascorbate generated 2-oxo-histidine but gave very low yields. Within chapter 3, a successful synthesis of protected 2-oxo-histidine is described, via the known imidazolin-2-one-4-carboxylic. Chapter 4 analyses Aβ(1-40) fibrillation kinetics by treating the intact peptide with various oxidants. Contrary to previous reports, hydrogen peroxide alone did not slow fibrillation rates. Cu(II)/Cu(I)- catalysed oxidation increased the likelihood of amorphous aggregation over fibrillation. This thesis shows oxidation of Aβ has a profound influence on fibril growth and that incorporation of a stable oxidised histidine into Aβ is a realisable goal.

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Alzheimer's disease (AD) is a neurodegenerative disorder that results in cognitive and functional impairment. Current pharmacological treatments have limited effect on correcting cognitive deficits. However, there is a growing amount of literature to suggest that lifestyle factors, such as physical activity, may have a positive effect on cognitive function for people with AD. Through a series of four articles I have addressed methodological short-comings in the existing literature, and determined, through collection and analysis of data in a longitudinal cohort study, the impact of lifestyle factors on cognitive performance in AD. Article I systematically reviews previous physical activity intervention trials and their effects on cognition in an AD population. Physical activity interventions were found to have a moderately positive effect on global cognition. However, the review highlights the apparent heterogeneity between intervention trials as well as the lack of domain specific cognitive outcome measures. Article II focuses on the importance of sensitive measures of cognition in an AD population. Comparing people with AD and age-matched control volunteers, measures of prospective memory were shown to decline with age in the AD volunteers. Significantly, the cost of carrying a PM intention, a measure of working memory, did not exhibit an age related decline and did not differ compared to cognitively healthy controls. Article III explores whether habitual physical activity, is significantly associated with cognitive outcome on a composite measures of executive function. Habitual physical activity significantly accounted for variance (8%) on executive function even after controlling for covariates. Article IV investigates the contribution of habitual physical activity to executive function change in AD over a year. Habitual physical activity was found to be associated with executive function change. These articles contribute in the understanding of the association between habitual physical activity and cognitive function in an AD population.

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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.

A challenge in the treatment of central nervous system (CNS) diseases is the transport of drug candidates into the brain. Inositol stereoisomers have show promise as therapeutic agents for CNS disorders. scyllo-Inositol was an effective prophylactic and therapeutic for Alzheimer’s disease (AD) in TgCRND8 mice, a model of AD. This suggests inositol stereoisomers have excellent CNS bioavailability. They enter the brain through inositol transporters, of which there are three: one hydrogen myo-inositol transporter (HMIT) and two sodium myo-inositol transporters (SMIT1, SMIT2). HYPOTHESIS: Given the high CNS bioavailability of inositol stereoisomers, it may be possible to use inositol transporters to shuttle other compounds into the CNS. OBJECTIVES: 1. To confirm the CNS bioavailability of the two main inositol stereoisomers, myo- and scyllo-inositol, in both TgCRND8 and wild-type mice. 2. To examine inositol transporter expression in the brains, as a function of time and disease pathology, in both groups. 3. To evaluate the flexibility of the inositol transporters for transporting compounds by determining the substrate structural features required for active transport. RESULTS: myo-Inositol and scyllo-inositol accumulated in the brain following oral administration. Disease pathology did not alter baseline inositol levels or uptake. Brain subregional transporter expression was unaltered as a function of age or disease pathology. In vitro cell culture experiments found HMIT inactive and therefore not a contender for drug transport. In contrast SMIT1 and SMIT2 were both active and competitive transport assays, revealed distinct criteria for active transport through each system. However, both were stringent in the substitutions to the structure of myo-inositol possible to maintain active transport. CONCLUSION: Active transport through the inositol transporters is very sensitive to changes in the structure of myo-inositol and only conservative changes are possible. Therefore, these transporters would not make effective shuttling systems for drug transport into the brain.