The present thesis explored a number of topics all linked by their involvement in Alzheimer’s disease (AD). Firstly, hippocampal slices prepared from a new transgenic knock-in mouse model of the disorder PLB1, harbouring human APP (with the Swedish and London mutations), Tau (with the P301L and R406W mutations) and PS1 (with the A246E mutation) genes were characterised electrophysiologically. Data obtained confirm AD-like alterations in PLB1 mice and suggest that these mice are a suitable model of AD and slice electrophysiology is a relevant experimental endpoint. Secondly, the effects of memantine on synaptic transmission and plasticity in the mouse hippocampus were investigated. Memantine was found to inhibit tetanus-induced LTP in the CA1 region at high concentrations (100 μM) while being devoid of such effects at lower (10 μM), therapeutically relevant doses. However, both concentrations acted to enhance baseline synaptic transmission via enhanced muscarinic signalling in a similar fashion to the muscarinic agonist carbachol, suggesting an additional facet to the drugs good clinical utility in AD patients. Thirdly, potential new treatments for AD were investigated in the form of a plant extract from <i>Cassia obtusifolia</i> (COE) and novel synthetic β-secretase (BACE) inhibitors LC25-116, LC25-120 and LC25-184. COE provided significant protection in models of excitotoxicity and mitochondrial dysfunction, both inherently linked to the pathogenesis of AD. The three novel BACE inhibitors significantly reduced Aβ production by an APP-expressing neuroblastoma cell line and reduced the resulting toxicity of its medium to hippocampal cultures. Finally, A1, a risk factor in AD, was investigated by assessing the toxicity of Al.cit.Q (K[A1(C₇H₁₁O₆)₃](OH]4H₂O_.The neuroprotective properties of quinic acid, the ligand attached to A1 in Al.cit.Q., were consequently tested. The results highlight the profound effect the ligand bound to A1 has on the metal’s toxicity and suggest that quinic acid could successfully be employed to combat metal toxicity.

Although a central etiology for Alzheimer disease (AD) has not yet been determined, support has amassed for the notion that oxidative stress may be involved in the pathogenesis of AD. The disruption of iron homeostasis and iron's excessive deposition in AD brain tissues has received increased attention due to the metal's capacity to promote the production of harmful free radicals. Several studies have recently examined whether DNA mutations involved in the iron overload disorder, hemochromatosis, pose an increased risk of acquiring AD. However, the small sample size and low generalizability of previous studies have warranted further investigation. We genotyped 213 AD patients, 106 Mild Cognitively Impaired (MCI) individuals, and 63 Normal Elderly Control (NEC) subjects for the H63D and C282Y HFE mutations to examine whether a relationship exists between HFE gene status and AD presentation in our patient population. DNA analysis was conducted by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). We did not find any statistically significant associations between HFE gene status and the clinical, demographic, or neuropsychological aspects of AD in our patient population. Interesting trends that fell short of statistical significance included: (a) a deleterious effect of HFE mutations on motor performance, (b) an influence of H63D homozygosity on an earlier onset of cognitive decline, and (c) an influence of H63D homozygosity on an accelerated progression from MCI to AD.

Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on Sep. 2, 2009). Includes bibliographical references.

No description available.

Alzheimer's disease (AD) is a worldwide, incurable disease, and the most common form of dementia. Numbers of cases are rising, and since its discovery the only approved medications have treated only the symptoms, not the pathological cause. With the cost to society rising, the debilitating nature of the disease and the pressure put on the family members and support network of patients, disease modifying therapies are in dire need. Current models have proven an invaluable tool with which to study certain aspects of the disease and the genetics behind it, however the lack of clinically approved medications in the last 20 years suggests new models are needed. Based on the amyloid cascade hypothesis, this thesis initially characterises two models of β-Amyloid oligomer (Aβo) induced cognitive deficits. Both models are created by ICV injection of soluble Aβo into the brain of rat. The models differ only by the molecular weight of the Aβo 1-42, one, referred to as low molecular weight (LMW) Aβo, with stable dimers, trimers and tetramers, the other, referred to as high molecular weight (HMW) Aβo, consisting of assemblies ranging from ~50 to ~150 kDa. It was found that behavioural deficits were similar between the two, with a robust object recognition deficit, but no working memory deficit. Both models also showed a deficit in the synaptic marker PSD-95; however the LMW Aβo caused a deficit in the frontal cortex, whereas the HMW Aβo caused a hippocampal deficit. The role of the cellular prion protein (PrPC) was explored, by blocking its binding to Aβo with the antibody 6D11. Interestingly the two models showed different results. The HMW Aβo deficits were completely blocked by the 6D11 application, however the LMW Aβo deficits were only partially prevented. Finally, Fasudil, a vasodilator approved in parts of Asia, was used to inhibit Rho-kinase, showing a prevention of the cognitive deficits in the HMW Aβo model. The results of this thesis show the ICV administration of Aβo to be a useful model for investigating the effects of Aβo, provides a platform with which to study the differing effects of Aβo with different oligomeric assemblies, and a model to test therapeutic strategies with relevance to AD.

Individuals with Alzheimer Disease (AD) exhibit deficits across multiple cognitive domains years before clinical diagnosis, when they are in the preclinical stages of the disease. Four studies were conducted to (a) examine the preclinical neuropsychological characteristics of English- and French-speaking Alzheimer Disease (AD) participants from the Canadian Study of Health and Aging (CSHA) and (b) determine the utility of select CSHA neuropsychological and demographic measures in predicting AD over a five-year period. Both English- and French-speaking AD participants demonstrated cognitive changes on episodic memory, verbal fluency, and speeded visuomotor processing tasks five years prior to diagnosis, however declines in performance between initial- and re-assessment were not uniform across these domains for either language group. Advanced age and declines in delayed episodic memory were the most significant indicators of progression to AD over a five-year period for both language groups. A validation study was conducted to investigate how well the predictors of AD prognosticate diagnostic outcome for an independent group of at-risk English-speaking participants. The best predictors of AD for the English-speaking group (age, episodic memory, and speeded visuomotor processing) accurately classified close to 70% of individuals from the at-risk sample. The present findings will contribute to diagnostic decisions regarding AD in older English- and French-speaking Canadian adults.

Individuals with Alzheimer Disease (AD) exhibit deficits across multiple cognitive domains years before clinical diagnosis, when they are in the preclinical stages of the disease. Four studies were conducted to (a) examine the preclinical neuropsychological characteristics of English- and French-speaking Alzheimer Disease (AD) participants from the Canadian Study of Health and Aging (CSHA) and (b) determine the utility of select CSHA neuropsychological and demographic measures in predicting AD over a five-year period. Both English- and French-speaking AD participants demonstrated cognitive changes on episodic memory, verbal fluency, and speeded visuomotor processing tasks five years prior to diagnosis, however declines in performance between initial- and re-assessment were not uniform across these domains for either language group. Advanced age and declines in delayed episodic memory were the most significant indicators of progression to AD over a five-year period for both language groups. A validation study was conducted to investigate how well the predictors of AD prognosticate diagnostic outcome for an independent group of at-risk English-speaking participants. The best predictors of AD for the English-speaking group (age, episodic memory, and speeded visuomotor processing) accurately classified close to 70% of individuals from the at-risk sample. The present findings will contribute to diagnostic decisions regarding AD in older English- and French-speaking Canadian adults.

A!dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in the fulfillment of the requirements for the degree of Master of Science. 2013. / Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting in excess of 26.6 million individuals globally. The neuropathological features of AD include extracellular deposition of amyloid beta (Aβ) plaques and intracellular neurofibrillary tangle formation. The cellular prion protein (PrPC) regulates the amyloidogenic cleavage pathway involved in Aβ shedding and interacts with the Aβ peptide. Given these interactions, the aim of this study was to investigate the influence of the 37kDa/67kDa laminin receptor (LRP/LR)- the cellular receptor for prion proteins- on Aβ shedding. Transfection of HEK293 cells with short hairpin RNAs (shRNAs) directed against LRP mRNA significantly decreased LRP levels in addition to Aβ shedding. Flow cytometric analysis revealed unchanged cell surface levels of the amyloid precursor protein (APP), β-secretase and γ-secretase after transfection of cells with shRNAs, suggesting a role of LRP/LR in Aβ shedding via a mechanism independent of gene-expression modulation of these key proteins. LRPshRNA treatment significantly reduced sAPPβ expression, implicating LRP/LR in APP processing specifically via augmenting the activity of β-secretase. Colocalisation of LRP/LR with APP, β- and γ-secretase, respectively, alludes to a possible interaction between said proteins. Therefore, LRP-shRNAs are suggested as alternative therapeutic tools for AD treatment.

The enzyme monoamine oxidase (MAO) is linked to mental disorders such as depression and neurodegenerative diseases. Our laboratory has recently demonstrated that increases in calcium (Ca2+) can enhance MAO activity and that this might contribute to Alzheimer disease (AD). AD has been linked to gain-of-function mutations in the presenilin-1 (PS-1) protein that not only promote the generation of the toxic amyloid-â peptide, but that also alter intracellular Ca2+ availability. <p>Radioenzymatic MAO assays were used to demonstrate that over-expression of different AD-related PS-1 mutant proteins, i.e. Y115H, ÄEx9 and M146V, in hippocampal-derived HT-22 cells alter either basal and/or Ca2+-sensitive MAO-A activity. The effects of PS-1 mutant proteins on the availability of intracellular Ca2+ are not consistent suggesting that this may not be the primary means of regulating MAO activity. The sensitivity of MAO to Ca2+ was also demonstrated in cortical (both MAO-A and MAO-B responded to Ca2+) and cerebellar (only MAO-A responded to Ca2+) samples from transgenic mice overexpressing the PS-1 (M146V) mutation. These changes in MAO coincided with changes in the availability of the neurotransmitters dopamine, noradrenaline and serotonin in the cerebellum, but not in the cortex, and reflect the known regional differences in neurotransmitter regulation. Immunoprecipitation studies and the observed increase in MAO-A activity following in vitro chemical inhibition of the ã-secretase complex (comprising several proteins including PS-1) support the notion that PS-1 constitutively associates with MAO-A. These effects on Ca2+-sensitive MAO function could contribute to AD-related pathology and could also contribute to the depression often associated with AD.

The enzyme monoamine oxidase (MAO) is linked to mental disorders such as depression and neurodegenerative diseases. Our laboratory has recently demonstrated that increases in calcium (Ca2+) can enhance MAO activity and that this might contribute to Alzheimer disease (AD). AD has been linked to gain-of-function mutations in the presenilin-1 (PS-1) protein that not only promote the generation of the toxic amyloid-â peptide, but that also alter intracellular Ca2+ availability. <p>Radioenzymatic MAO assays were used to demonstrate that over-expression of different AD-related PS-1 mutant proteins, i.e. Y115H, ÄEx9 and M146V, in hippocampal-derived HT-22 cells alter either basal and/or Ca2+-sensitive MAO-A activity. The effects of PS-1 mutant proteins on the availability of intracellular Ca2+ are not consistent suggesting that this may not be the primary means of regulating MAO activity. The sensitivity of MAO to Ca2+ was also demonstrated in cortical (both MAO-A and MAO-B responded to Ca2+) and cerebellar (only MAO-A responded to Ca2+) samples from transgenic mice overexpressing the PS-1 (M146V) mutation. These changes in MAO coincided with changes in the availability of the neurotransmitters dopamine, noradrenaline and serotonin in the cerebellum, but not in the cortex, and reflect the known regional differences in neurotransmitter regulation. Immunoprecipitation studies and the observed increase in MAO-A activity following in vitro chemical inhibition of the ã-secretase complex (comprising several proteins including PS-1) support the notion that PS-1 constitutively associates with MAO-A. These effects on Ca2+-sensitive MAO function could contribute to AD-related pathology and could also contribute to the depression often associated with AD.