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.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 4 uppsatser.

by Lan Chen. / "June 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

by Tam Shuk Yin, Jeanny. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 26-29). / Abstract and appendix in English and Chinese. / ABSTRACT --- p.ii / ACKNOWLEDGEMENTS --- p.iii / TABLE OF CONTENTS --- p.iv / LIST OF TABLES --- p.v / LIST OF FIGURES --- p.vi / Chapter CHAPTER I - --- INTRODUCTION --- p.1 / Chapter CHAPTER II - --- METHOD --- p.5 / Chapter CHAPTER III - --- RESULTS --- p.12 / Chapter CHAPTER IV - --- DISCUSSION --- p.22 / REFERENCES --- p.26 / APPENDICES --- p.30

by Ma Suk Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 106-129). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Acknowledgements --- p.v / Publications --- p.vi / Abbreviations --- p.vii / Chapter Chapter 1 --- General Introduction --- p.1 / Chapter 1.1 --- Epidemiology of AD --- p.2 / Chapter 1.2 --- Clinical and pathological features of AD --- p.3 / Chapter 1.2.1 --- Clinical features of AD --- p.3 / Chapter 1.2.2. --- Pathological features of AD --- p.3 / Chapter 1.3 --- Diagnosis of AD --- p.4 / Chapter 1.4 --- Classification of AD --- p.5 / Chapter 1.5 --- Causes of AD --- p.5 / Chapter 1.6 --- Risk factors --- p.5 / Chapter 1.6.1 --- Age --- p.5 / Chapter 1.6.2 --- Family history --- p.6 / Chapter 1.6.3 --- Genetics --- p.6 / Chapter 1.6.3.1 --- Autosomal dominant mutations --- p.6 / Chapter 1.6.3.2 --- Genotypes of Apolipoprotein E --- p.6 / Chapter 1.6.4 --- Environmental factors --- p.7 / Chapter Chapter 2 --- Pathology in Alzheimer's disease --- p.8 / Chapter 2.1 --- Overview of Alzheimer's disease pathology --- p.8 / Chapter 2.2 --- Amyloid plaques --- p.8 / Chapter 2.2.1 --- Amyloid precursor protein --- p.8 / Chapter 2.2.2 --- Processing ofAPP --- p.9 / Chapter 2.2.3 --- Amyloid β (Aβ) --- p.12 / Chapter 2.2.4 --- APP mutations and AD --- p.12 / Chapter 2.3 --- Neurofibrillary tangles (NFT) --- p.15 / Chapter 2.3.1 --- Tau --- p.15 / Chapter 2.3.2 --- Tau mutation and neurodegeneration --- p.17 / Chapter 2.4 --- Hypotheses for AD pathology --- p.18 / Chapter 2.4.1 --- Amyloid cascade hypothesis --- p.18 / Chapter 2.4.2 --- Inflammatory hypothesis --- p.20 / Chapter 2.4.2.1 --- Microglia and astrocytes --- p.21 / Chapter 2.4.2.2 --- Inflammatory cytokines --- p.23 / Chapter 2.4.2.3 --- Inflammation and AD --- p.25 / Chapter 2.4.3 --- ApoE hypothesis --- p.27 / Chapter 2.4.3.1 --- Apolipoprotein E --- p.27 / Chapter 2.4.3.2 --- ApoE and AD --- p.28 / Chapter 2.5 --- Theory towards the pathology of AD --- p.30 / Chapter Chapter 3 --- ApoE genotyping --- p.32 / Chapter 3.1 --- Introduction --- p.32 / Chapter 3.2 --- Materials and methods --- p.32 / Chapter 3.2.1 --- Patients and control subjects --- p.32 / Chapter 3.2.2 --- Blood sampling --- p.33 / Chapter 3.2.3 --- DNA genotyping --- p.34 / Chapter 3.2.4 --- Statistical analysis --- p.35 / Chapter 3.3 --- Results --- p.35 / Chapter 3.. --- Discussion --- p.38 / Chapter Chapter 4 --- IL-1β polymorphism in relation to the risk of ADin Chinese --- p.39 / Chapter 4.1 --- Introduction --- p.39 / Chapter 4.2 --- Materials and methods --- p.44 / Chapter 4.2.1 --- Patients and control subjects --- p.44 / Chapter 4.2.2 --- Blood sampling --- p.44 / Chapter 4.2.3 --- DNA genotyping --- p.44 / Chapter 4.2.4 --- Statistical analysis --- p.48 / Chapter 4.3 --- Results --- p.48 / Chapter 4.4 --- Discussion --- p.53 / Chapter Chapter 5 --- TNFα polymorphism in relation to the risk of ADin Chinese --- p.63 / Chapter 5.1 --- Introduction --- p.63 / Chapter 5.2 --- Materials and methods --- p.66 / Chapter 5.2.1 --- Patients and control subjects --- p.66 / Chapter 5.2.2 --- Blood sampling --- p.66 / Chapter 5.2.3 --- DNA genotyping --- p.66 / Chapter 5.2.4 --- Haplotype determination --- p.70 / Chapter 5.2.5 --- Statistical analysis --- p.70 / Chapter 5.3 --- Results --- p.70 / Chapter 5.4 --- Discussion --- p.75 / Chapter Chapter 6 --- LRP8 polymorphism in relation to the risk of ADin Chinese --- p.81 / Chapter 6.1 --- Introduction --- p.81 / Chapter 6.2 --- Materials and methods --- p.87 / Chapter 6.2.1 --- Patients and control subjects --- p.87 / Chapter 6.2.2 --- Blood sampling --- p.87 / Chapter 6.2.3 --- DNA genotyping --- p.87 / Chapter 6.2.4 --- Statistical analysis --- p.89 / Chapter 6.3 --- Results --- p.91 / Chapter 6.4 --- Discussion --- p.98 / Chapter Chapter 7 --- Conclusions and prospects for future work --- p.102 / Chapter 7.1 --- Conclusion --- p.102 / Chapter 7.2 --- Prospects for future work --- p.105 / Reference --- p.106

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.

Alzheimer’s disease (AD) has been defined as a type of dementia that causes problems with memory, thinking, and behavior. AD is characterized by tau tangles and Aβ plaques in and around neurons, respectively. The impact this disease has on its victims’ health, both physically and mentally, is unimaginable and the rate of progression is not expected to decrease any time soon. This threat to our minds encourages the importance of understanding AD. Amongst the theories as to what bio mechanisms cause the brain to intertwine is the amyloid cascade hypothesis. The purpose of this thesis is to review the amyloid cascade hypothesis and discuss treatments which utilize this model. We also wish to examine social aspects such as loneliness and socioeconomic factors which are associated with the progression of AD. Research presented provides evidence that targeting the accumulation of Aβ in the brain will prevent further biochemical responses to form neurodegenerative pathology. From the collected data, we observe that therapies targeting the amyloidogenic pathway have received positive feedback in the medical community. Amongst them, an Aβ synthetic peptide vaccine which made history in vaccine development due to their responder rate. The impact of social factors such as loneliness in the advancement of AD is also supported by research. While it is acknowledged that any neurodegenerative disease is far too complex to narrow its cause specifically, this thesis provides an association with multiple aspects that can be understood and applied to future research in this field. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Au May Lan Alma Mary Gerardina. / "August 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 68-73). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Kwan Shuk-ying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 101-109). / Abstracts in English and Chinese. / ABSTRACT --- p.I / 摘要 --- p.III / ACKNOWLEDGEMENT --- p.V / TABLE OF CONTENTS --- p.VI / ABBREVIATION --- p.IX / LIST OF TABLES --- p.X / LIST OF FIGURES --- p.XI / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Alzheimer's disease - a growing health problem in Hong Kong --- p.2 / Chapter 1.2 --- Pathology of Alzheimer's disease --- p.3 / Chapter 1.3 --- Clinical features of Alzheimer's disease --- p.6 / Chapter 1.4 --- Clinical diagnosis of Alzheimer's disease --- p.9 / Chapter 1.5 --- Background and objectives of study --- p.10 / Chapter 1.6 --- Outlines of the Thesis --- p.11 / Chapter CHAPTER 2 --- NUTRITIONAL ASPECTS OF ALZHEIMER'S DISEASE --- p.12 / Chapter 2.1 --- Introduction --- p.13 / Chapter 2.2 --- Weight loss in Alzheimer's disease patients --- p.14 / Chapter 2.3 --- "Weight loss, morbidity and mortality" --- p.15 / Chapter 2.4 --- Factors contribute to weight loss --- p.17 / Chapter 2.4.1 --- Progress of Alzheimer's disease --- p.17 / Chapter 2.4.2 --- Biological factors --- p.17 / Chapter 2.4.3 --- Biochemical factors --- p.21 / Chapter 2.4.4 --- Psychosocial factors --- p.26 / Chapter 2.5 --- Background of study --- p.28 / Chapter CHAPTER 3 --- METHODOLOGY --- p.30 / Chapter 3.1 --- Subject recruitment --- p.31 / Chapter 3.2 --- Ethical Approval --- p.31 / Chapter 3.3 --- Nutritional assessments --- p.32 / Chapter 3.4 --- Cognitive assessments --- p.39 / Chapter 3.5 --- Factors Associated with Nutritional Status --- p.42 / Chapter 3.5.1 --- Biological factors --- p.42 / Chapter 3.5.2 --- Biochemical factors --- p.52 / Chapter 3.5.3 --- Psychosocial factors --- p.57 / Chapter 3.6 --- Statistical Analysis --- p.59 / Chapter CHAPTER 4 --- RESULTS --- p.62 / Chapter 4.1 --- Demographic characteristics --- p.63 / Chapter 4.2 --- Nutritional assessments --- p.64 / Chapter 4.3 --- Factors associated with Nutritional Status --- p.66 / Chapter 4.3.1 --- Biological factors --- p.66 / Chapter 4.3.2 --- Biochemical factors --- p.68 / Chapter 4.3.3 --- Psychosocial factors --- p.68 / Chapter 4.4 --- Longitudinal observations --- p.70 / Chapter CHAPTER 5 --- DISCUSSION --- p.84 / Chapter 5.1 --- Nutritional Status --- p.85 / Chapter 5.1.1 --- Cross-sectional Study --- p.85 / Chapter 5.1.2 --- Longitudinal Observations --- p.86 / Chapter 5.2 --- Factors associated with Nutritional Status --- p.88 / Chapter 5.2.1 --- Biological factors --- p.88 / Chapter 5.2.2 --- Biochemical factors --- p.92 / Chapter 5.2.3 --- Psychosocial factors --- p.95 / Chapter CHAPTER 6 --- CONCLUSION --- p.98 / REFERENCES --- p.101 / Appendix 1 Clinical Diagnosis of Alzheimer's disease --- p.110 / Appendix 2 Consent Form --- p.111 / Appendix 3 Mini Nutritional Assessment --- p.115 / Appendix 4 Mini Mental State Examination --- p.118 / Appendix 5 Functional Assessment Staging (FAST) --- p.119 / Appendix 6 Physical Activity Questionnaire (PAQ) --- p.120 / Appendix 7 3-day Dietary Record --- p.129 / Appendix 8 Olfactory Function Test --- p.134 / Appendix 9 Neuropsychiatric Inventory (NPI) --- p.138 / Appendix 10 The Chinese version of Neuropsychiatric Inventory …… --- p.151

Abstract Alzheimer’s disease (AD) is a major public health concern worldwide, with an increasing prevalence in the elderly population. AD is a progressive neurological disorder of multi-faceted origin, where factors such as genetic mutations, biochemical changes, along with inflammatory cascade and soluble beta amyloid (Aβ) peptide, are thought to play a pivotal role in synaptic failure and neuronal death, ultimately leading to cognitive and neuropsychiatric decline in patients suffering from the disease. At present, there is no long-term cure for the disease, although there is access to pharmacotherapy that might improve cognitive and neuropsychiatric symptoms early in the course of the disease. The current pharmacological therapy for AD only provides symptomatic relief for a very short period of time. It is therefore of utmost importance to discover other pharmacological strategies that might delay the development of AD and slow down the disease progression in terms of cognitive decline and neurodegeneration. Elucidating the pathogenic mechanisms involved in AD neuropathogenesis is a major goal to find efficacious disease-modifying treatments. What remains to be understood completely are the intracellular pathways affected by Aβ protein which may lead to neurodegeneration in AD. Since phosphorylation and dephosphorylation mechanisms are crucial in the β-amyloid precursor protein (APP) metabolism, protein kinase C has emerged as one of the key regulators of the APP metabolism. Indeed, dysregulation of the PKC pathway might play a role in the intracellular mechanisms of neurodegeneration, but their effective involvement still remains elusive. Therefore, a detailed analysis of PKC pathways in established models of AD neurodegeneration is necessary and will form part of this work. Fucoidin is a sulphated polysaccharide extracted from edible brown seaweed, which has been shown to exhibit anti-inflammatory and anti-oxidant effects as well as being a neuroprotectant in various inflammatory diseases including hypoxic ischemia, atherosclerosis and Heyman nephritis. Therefore, fucoidin may have an inhibitory effect on the inflammatory mechanisms of AD. Little is known, however, about the effect of fucoidin on AD. Animal models of AD are extremely valuable for the discovery and development of new treatments. Rodents have been one of the preferred models for pharmacological and behavioural studies in AD. In this thesis, first aim was to establish a non-transgenic Aβ-induced AD model in rats. AD was induced utilising a published protocol which involved the bilateral injection of aggregated Aβ (1-42) into the CA3 subfield of the hippocampus in rat brain. Behavioural assessment with well defined tools such as the Morris water maze and T-maze were utilised to assess the impairment in spatial working memory in rats. Behavioural impairments along with increased astrocytosis and microgliosis were observed in this particular Aβ-induced AD model. In the established disease model, fucoidin (50 mg/kg/day and 25 mg/kg/day) and ibuprofen (50 mg/kg/day) were shown to provide a partial protective effect on impairment in memory function in the MWM behavioural task in rats treated prior to disease initiation and throughout the course of the study. In addition, the histopathological and quantitative analysis of AD brain sections showed a marked reduction in reactive glial fibrillary acidic protein (GFAP) and microglia in fucoidin (low and high dose) and ibuprofen treated Aβ injected rats compared to untreated Aβ injected rats. These results indicate that fucoidin may serve as a possible effective therapeutic approach to improve AD symptoms. There is strong evidence that PKC α and ε signalling pathways regulate important molecular events in memory impairment and neurodegenerative pathophysiology in AD. A possible neuroprotective mechanism of fucoidin involving attenuation of an Aβ-induced decrease in PKC ε phosphorylation using cultured SHSY5Y neuroblastoma cells as a model system was examined. Co-administration of fucoidin (2μM and 5 μM) with Aβ (1μM) abolished the inhibitory effect of Aβ on the phosphorylation of PKCε in a concentration-dependent manner as revealed by western blot analysis. These findings suggest that a possible mechanism underpinning the neuroprotective effect of fucoidin may be through prevention of A-induced inhibition of PKC phosphorylation and may serve as a possible therapeutic approach to improve AD symptoms. As cellular events that involve PKC are affected by Aβ in in vitro systems, it was necessary to examine whether PKC activity is also modulated by the Aβ treatment in vivo in our Aβ-peptide induced AD model. Therefore, the next aim was to assess the potential for fucoidin use as an intervention therapy in an established disease stage in the Aβ-peptide induced AD model. Intervention with fucoidin (50 mg/kg/day, i.p.) in the established disease stage partially prevented Aβ (1-42) mediated damage with respect to memory impairment, neuroinflammation and PKC ε phosphorylation in the in vivo AD model consistent with the in vitro findings in SHSY5Y cells.