阿茲海默症基因多型性之遺傳分析暨改善疾病藥物之篩選

Association Study and Drug Screening for Alzheimer's Disease

劉書祥(Shu-Hsiang Liu)

指導教授 ： 王建國

亞洲大學/健康學院/生物科技學系碩士班/碩士(2009年)

摘要

阿茲海默症 (Alzheimer's disease, AD)，又稱老年痴呆症，是一種持續性退化的神經性疾病。目前致病機轉尚不明瞭，所以尚無有效診斷疾病及治療的方法，最早在1906年由Alois Alzheimer醫生描述此病症。他藉著病理解剖觀察到病人有斑塊 (amyloid plaques) 和纏結 (neurofibrillary tangles) 的腦部變化，兩者皆會阻斷腦部神經訊息傳遞的功能。到了1980年代研究者辨識了斑塊和纏結分別是由類澱粉蛋白 (β-amyloid) 與microtubule-associated蛋白tau聚集所組成，兩者的形成被認為與AD患者的腦部神經元退化以及疾病發生有關。本研究是利用單一核苷酸多型性 (single nucleotide polymorphism，簡稱SNP) 的分析來探討與AD高度相關的可能致病基因，及以基因轉殖疾病果蠅模式來篩選可能具改善疾病的藥物。在SNP的研究中，分析了COMT、DAT1、DRD4、GRIN3A、GRIN3B、PARP1基因變異與AD患者的相關性，我們共完成了在台灣的120位晚發型 (late-onset) 65歲以上的AD患者做為實驗組，另有86位健康族群做為對照組。研究結果顯示DAT1、DRD4、GRIN3A、PARP1基因與台灣AD患者具有高度相關性，因此可能可以做為發病傾向的遺傳標記 (genetic marker)。另外，利用果蠅疾病動物模式來篩選改善疾病之藥物。實驗結果顯示七組藥物的初步分析發現，三組藥物對疾病果蠅的存活率，在統計學上有顯著差異。日後可針對這三組藥物測試適當之濃度，也可以更進一步探討其可能的作用機制。

關鍵字

阿茲海默症 ； 單一核苷酸多型性

並列摘要

Alzheimer's disease (AD), also named dementia, a progressive neurodegenerative disease. This incurable disease was first described by German psychiatrist Alois Alzheimer in 1906. He observed two pathological characters, amyloid plaque and neurofibrillary tangles, from the patient’s brain section, and suggested that these aggregates may affect the neuron transmission and brain function. In 1980s, researchers identified the components of amyloid plaque and neurofibrillary tangle are β-amyloid and microtubule-associated protein tau, respectively, causing neuron degeneration and AD pathogenesis. In this study, association study was performed to determine the relationships between several potential genes and the susceptibility of AD by analyzing single nucleotide polymorphism (SNP) variations and also using AD transgenic fly model to screen the potential drugs to improve the disease progression. In SNP study, to demonstrate the potential association of COMT, DAT1, DRD4, GRIN3A, GRIN3B, and PARP1 gene polymorphisms with AD, we performed the case-control study enrolling 120 AD patients and 86 normal controls. These data suggest that genetic variations of the DAT1, DRD4, GRIN3A, and PARP1 genes may be genetic factors to modulate the pathogenesis of AD in Taiwanese population.
Moreover, we have analyzed seven kinds of drugs, and three of them may cause the changes of life span in our experiments of fly model. Furthermore, we will study the appropriate concentration and understand their roles involved in the development of AD.

並列關鍵字

Alzheimer's Disease ； single nucleotide polymorphism

參考文獻

Abbott, A. (2008). "Neuroscience: The plaque plan." Nature 456

Akama, K. T., C. Albanese, et al. (1998). "Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism." Proc Natl Acad Sci U S A 95(10): 5795-800.

Altshuler, D., M. J. Daly, et al. (2008). "Genetic mapping in human disease." Science 322(5903): 881-8.

Arvin, B., L. F. Neville, et al. (1996). "The role of inflammation and cytokines in brain injury." Neurosci Biobehav Rev 20(3): 445-52.

Ballatore, C., V. M. Lee, et al. (2007). "Tau-mediated neurodegeneration in Alzheimer's disease and related disorders." Nat Rev Neurosci 8(9): 663-72.