Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2003. / Vita. Includes bibliographical references (leaves 74-84).

No description available.

The 5XFAD mouse is a double transgenic model of Alzheimer’s disease (AD), which harbors a human amyloid precursor protein transgene with three mutations (K670N/M671L, I716V, V717I) and a human presenilin-1 transgene with two mutations (M146L, L286V). These mutations act additively to produce large amounts of amyloid-beta (A?) and rapid development of AD-related pathology, including A?-plaques, neuroinflammation, synapse loss, impaired synaptic plasticity and death of layer 5 cortical neurons (Oakley et al., 2006, J. Neurosci., 26, 10129-10140). Despite the extensive characterization of neuropathology in the 5XFAD mouse, much less research has been completed characterizing age-related changes in behaviour. Sex, the albinism producing tyrosinase mutation (Tyrc), the retinal degeneration phosphodiesterase 6b mutation (Pde6brd1) and the limb-girdle muscular dystrophy 2B dysferlin mutation (Dysfim) are genetic factors present in the background strain (C57BLxSJL) of the 5XFAD mouse and other AD models. However, background genetic factors are rarely controlled, and their influence on AD-related behavioral phenotypes is largely unknown. Therefore, the objectives of this thesis were to characterize age-related changes in behaviour of the 5XFAD mouse, and determine the extent to which background genetic factors influence the expression of AD-related behavioral phenotypes. Male and female 5XFAD and wild-type (WT; C57BL6xSJL F2) mice completed a behavioural test battery at 3-4, 6-7, 9-10, 12-13 and 15-16 months of age in a cross-sectional experimental design. In experiment 1, motor ability was assessed with the open-field (locomotor activity), rota-rod (motor coordination and learning), balance beam (balance) and the wire and grid suspension tests (grip-strength). 5XFAD mice weighed less than WT mice at 9-15 months of age, and also reared less on the open-field and performed worse on the rota-rod. 5xFAD mice also travelled less distance on the open-field, fell faster on the balance beam and showed impaired grip-strength at 12-13 months of age. The Dysfim mutation has been previously shown to produce muscular weakness and impair motor function, but mutant Dysfim did not impair the motor performance of either WT or 5XFAD mice. In experiment 2, 5XFAD and WT mice were tested on the Morris water maze to assess visuo-spatial learning and memory. 5XFAD mice were impaired in acquisition and reversal learning, but not memory at 6 and 9 months of age. Motor impairments in 5XFAD mice impaired swimming ability and confounded learning and memory performance of mice at 12 and 15 months. Female mice performed worse than male mice, and albino mice performed worse than pigmented mice, demonstrating that background genetic factors influence the performance of mice on the Morris water maze. In experiment 3, olfactory learning and memory was assessed with an olfactory digging discrimination test. 5XFAD mice did not differ from WT mice in memory performance at any age tested. We then examined A? plaque pathology in 5XFAD mice and confirmed the presence of A? deposits in brain regions associated with motor function and learning and memory. Very few A? deposits were present in the cerebellum suggesting plaque pathology in the basal ganglia and/or motor cortex impairs motor function. Extensive A? plaque deposition was also found in the olfactory memory system despite the lack of olfactory memory impairment in 5XFAD mice. These results indicate that the 5XFAD mouse is a useful model for A?-pathology, cognitive and motor impairments observed in AD, but it is required that sex and albinism are properly controlled in the assessment of cognitive function.

Infrared microspectroscopy has been used to survey Alzheimer’s diseased brain tissue from a transgenic mouse model of the disease. Alzheimer’s disease is the leading cause of dementia among the elderly and is characterized by β-amyloid plaque deposition,neurofibrillary tangles, inflammation, and disturbed energy metabolism in the brain. Both the TgCRND8 and Tg19959 mouse models of the disease develop Alzheimer’s disease pathology beginning at approximately 3 months of age. Infrared microspectroscopy allows analysis of untreated, flash frozen tissue samples, at micron level spatial resolution, and was used in this study to examine creatine deposits in the Alzheimer’s diseased brain. Creatine is central to cellular energetics and plays an important role in proper brain function. The hippocampi of 7 pairs of transgenic mice and their littermate controls were mapped using infrared microspectroscopy and the results were analyzed for creatine levels and levels of β-sheet, indicative of the presence of β-amyloid plaques. Creatine was found to be focally elevated in the transgenic mice, as compared to their littermate controls but was not co-localized with β-amyloid plaques. Further surveys of serial sections from one transgenic mouse showed the 3-dimensional distribution of creatine within the sample. Focally elevated creatine may be a marker of the disease process, indicative of disturbed energy metabolism or inflammatory response to the disease progression.

No description available.

Alzheimer’s disease (AD) is the most reoccurring type of dementia, and remains incurable. Much work has been done to investigate the connections between AD development, type 2 diabetes and insulin receptor signaling abnormalities. Full length amyloid precursor protein (flAPP) is a large transmembrane protein that has significant physiological activities including in utero fetal development. Alpha secretase enzymes cleave flAPP, producing secreted amyloid precursor protein alpha (sAPPα), which has neuroprotective properties, including protection against neuronal apoptosis as well as the induction of neuronal outgrowth. There is no known dedicated receptor for the physiological action of sAPPα. Our data suggest that the physiological actions of sAPPα are a result of the physical interaction between sAPPα and the neuronal insulin receptor. We have shown that sAPPα phosphorylates, and thus activates, the neuronal insulin receptor as well as specific downstream proteins, including insulin receptor substrate (IRS), and protein kinase B (Akt). We have also shown that the observed interaction between sAPPα and neuronal insulin receptors is physical and that sAPPα competes with insulin for the insulin binding site. These findings may have implications for therapies aimed at slowing down the progression of AD through the activation of the insulin receptor pathway, since in neurons, insulin and the insulin receptor pathway are critical to the neuronal health and plasticity.

Infrared microspectroscopy has been used to survey Alzheimer’s diseased brain tissue from a transgenic mouse model of the disease. Alzheimer’s disease is the leading cause of dementia among the elderly and is characterized by β-amyloid plaque deposition,neurofibrillary tangles, inflammation, and disturbed energy metabolism in the brain. Both the TgCRND8 and Tg19959 mouse models of the disease develop Alzheimer’s disease pathology beginning at approximately 3 months of age. Infrared microspectroscopy allows analysis of untreated, flash frozen tissue samples, at micron level spatial resolution, and was used in this study to examine creatine deposits in the Alzheimer’s diseased brain. Creatine is central to cellular energetics and plays an important role in proper brain function. The hippocampi of 7 pairs of transgenic mice and their littermate controls were mapped using infrared microspectroscopy and the results were analyzed for creatine levels and levels of β-sheet, indicative of the presence of β-amyloid plaques. Creatine was found to be focally elevated in the transgenic mice, as compared to their littermate controls but was not co-localized with β-amyloid plaques. Further surveys of serial sections from one transgenic mouse showed the 3-dimensional distribution of creatine within the sample. Focally elevated creatine may be a marker of the disease process, indicative of disturbed energy metabolism or inflammatory response to the disease progression.

Of the three forms of human Apolipoprotein E (ApoE2, ApoE3 and ApoE4), the ?4 allele coding for ApoE4 is associated with a higher risk of developing Alzheimer's disease (AD) and an earlier age of onset, whereas ?2 may be protective. The mechanisms underlying such influences are still unclear. This thesis has investigated the influence of ApoE polymorphism on structural synaptic parameters in the middle molecular layer (MML) of the dentate gyrus of wild type (WT), ApoE knockout (KO) and human ApoE (hApoE) transgenic mice, from 6 to 24 months of age using unbiased stereological methods at the EM level. In hApoE4 mice, there was a 34% decrease in the synapse per neuron ratio (Syn/nrn) accompanied by a 22% increase in the mean apposition zone area (mAZA) during aging. This pattern resembles closely the synaptic changes occurring early in AD, which have been correlated to the first symptoms of memory loss in humans. In contrast. there was no such synaptic loss in hApoE2, ApoE KO and WT mice. At old age, hApoE4 mice had the lowest syn/nrn but their mAZA was comparable to that of other groups. These data appear to be consistent with the view that possession of ?4 is deleterious to cognitive functions in the elderly and AD patients. Notably, aged ApoE KO mice did not show any sign of synaptic degeneration, suggesting the involvement of other proteins to compensate for the lack of ApoE. At 18 months old, hApoE2 mice have a greater hippocampal volume and display the highest syn/nrn and glutamate immunogold labelling in presynaptic boutons and dendrites of the MML, compared to hApoE3 and hApoE4 mice. In AD patients, such effects of the ?2 allele may act as a synaptic 'reservoir' and delay the onset of AD symptoms. Thus these lines of hApoE transgenic mice could provide a good basis for the future production of multiple transgenic mice in which to model AD pathogenesis.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 158-171).

Thesis (M.S.) -- Worcester Polytechnic Institute. / Keywords: Alzheimer's; Ependymins; Caspases; SOD. Includes bibliographical references (p. 55-59).