Alzheimer's disease (AD) is the most common form of dementia, currently affecting around 17--25 million people worldwide. The typical neuropathological hallmarks of AD are amyloid beta (Abeta) deposition, presence of neurofibrillary tangles and neuronal cell death. Evidence from ongoing studies on the pathogenesis of AD, suggests that several different mechanisms are involved in neurons loss and thus decline of cognitive function. These include the metabolism of amyloid peptide, inflammation, cholesterol metabolism, and hormonal factors. / I have focused on the role of inflammation in the progression of AD. The inflammation hypothesis is based on findings of (1) elevated levels of inflammatory cytokines, such as IL-1, IL-6, TNFalpha, (2) the reduced levels of anti-inflammatory cytokines, like IL-10 in CSF and the blood of AD patients, and (3) activated microglia in the histological section of the patient's brain. On the other hand, the effects of the ApoE gene and differential age of onset between the two sexes suggested a modulation role for cholesterol and sex hormone like estrogen, which may influence the inflammatory response in the brain, so as to modulate the risk of AD. / In this project, the genetic risk factors predisposing to AD were investigated by genetic association studies of candidate genes. Candidate genes were shortlisted by two approaches. (I) Linkage-based candidate genes: Candidate genes were identified from reported loci with linkage to AD genome scan studies. Previous linkage studies of AD families revealed linked loci at 1p36, 1q23, 3p14, 4q32, 6p21, 6q27, 9q22, 10q24, 13q32, 15q26, 19q13 and 21q22. Several candidate genes from these loci including TNFalpha-related genes, TLR2, IGF-1, IFNalpha and MTHFR were selected for this project. (II) Hypothesis-based candidate genes: Candidate genes were selected according to their possible involvement in the inflammation hypothesis of AD. Under the hypothesis-based candidate gene approach, genes that might contribute to the inflammatory response of amyloid deposition were identified. These genes were validated by their expression level in the central nervous system. A further priorization step was carried out to select those genes showing a higher degree of inter-individual variation. Therefore, these genes were more likely to have a genetic/inherited variation at the population level. In other words, they are more likely to be the predisposition genes than genes without inter-individual variation (house-keeping genes are examples of genes showing little inter-individual variation). In this project, genes involved in the inflammatory pathway in the brain, such as IL-10 and HLA-A, and also genes that interact with the inflammatory pathway such as cholesterol related enzymes and estrogen receptors were investigated under the hypothesis-based approach. / This project is based on a case-control genetic association study which comprised of NINCDS-ADRDA diagnosed Chinese patients with AD (n=259) and age-matched non-demented subjects (n=248). Three genes PTGS2 (encoding for COX-2), MxA and ESR1 were selected for an intensive study by investigating their linkage disequilibrium pattern and using tagSNP strategy. TagSNPs selected for each gene were genotyped to investigate their association with the risk of AD. / This study showed that MTHFR, IL-10, HLA-A, CYP46A1, PTGS2 (COX-2) and ESR1 were associated with the risk of AD, and MxA, identified for the first time, was associated with the age of onset of AD. In conclusion, the results of my study further suggested the roles of inflammation in the pathogenesis of AD. / Ma Suk Ling. / "June 2006." / Advisers: Linda C. W. Lam; Nelson L. S. Tang. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1417. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 169-204). / 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, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_343875 |
| Date | January 2006 |
| Contributors | Ma, Suk Ling., Chinese University of Hong Kong Graduate School. Division of Medical Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xvi, 204 p. : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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