臺灣博碩士論文加值系統

阿滋海默氏症是目前最常見的神經退化性疾病，全球有超過兩千萬名病患，而阿滋海默氏症形成的主因是一段稱為amyloid-beta的胜肽鏈的不正常摺疊以及聚集。在我們的研究中，我們利用人工合成的Abeta1-42胜肽在in vitro的狀況下製備Abeta1-42 fibril以及oligomer，並且以原子力顯微鏡觀察其結構以及其形成的過程。我們發現Abeta1-42 oligomer會堆疊形成圈狀或者是球形的結構，而Abeta1-42 fibril則會進行漸進的成熟過程，彼此互相纏繞而形成更加緻密的纖維。在對未成熟神經元的毒性分析方面，我們發現只有Abeta1-42 oligomer會對大白鼠大腦皮質神經元具有毒性並造成細胞死亡，而Abeta1-42 fibril則無類似毒性。Abeta1-42 fibril以及oligomer影響未成熟神經元的結構方面，我們發現Abeta1-42 fibril以及oligomer都會附著到神經細胞的突觸，但是只有Abeta1-42 oligomer會造成神經元neurite的斷裂以及pre-synaptic protein (synapsin I)的不正常聚集。在Abeta1-42 oligomer處理的細胞中，NMDA receptor 1以及tau的蛋白質表現量都會上升，我們也發現Abeta1-42 oligomer會導致tau的過度磷酸化而使微小管的結構不穩定。另一方面，在成熟神經元的實驗中，我們還發現Abeta1-42 oligomer會抑制由NMDA所導致的鈣離子流入和降低synapsin I的表現，而苯基偶氮苯磺胺類衍生物會因其抑制Abeta1-42 oligomer的形成而降低其所造成成熟神經元synapsin I減少的現象。

Alzheimer’s disease is the most common neuron degenerative disease with more than 20 million cases world wide. This disease is caused by misfolding and aggregation of a small peptide amyloid-��. In our study, we prepared Abeta1-42 fibrils and oligomers by artificially synthesized Abeta1-42 peptide in vitro. The structure and maturation processes were analyzed by atomic force microscopy. We found that Abeta1-42 oligomer was stacked into doughnut-like or globular structure, and Abeta1-42 fibril underwent a progressive maturation processe by self-twisting. The toxicological study showed that only Abeta1-42 oligomer, but not Abeta1-42 fibril, was toxic to immature primary rat cortical neurons and caused cell necrosis. We also proved that both Abeta1-42 fibril and oligomer attached to the immature-synaptic structure. However, only Abeta1-42 oligomer caused neurite fragmentation and induced aggregation of pre-synaptic protein synapsin I. Abeta1-42 oligomer also induced overexpression of NMDA receptor1 and microtubule associate protein tau. Our study on tau phosphorylation in the immature neurons also showed that Abeta1-42 oligomer induced tau hyper-phosphorylation. In the mature neurons, Abeta1-42 oligomer reduced NMDA-induced calcium influx and reduced the level of synapsin I. Six phenylazo benzenesulfonamide compounds were able to inhibit Abeta1-42 oligomer formation and protected neurons against Abeta1-42 oligomer-induced reducing of synapsin I.

圖表目錄.......................................... II
縮寫表.............................................IV
中文摘要...........................................VI
英文摘要...........................................VII
緒論...............................................1
目的...............................................14
實驗材料...........................................15
實驗方法...........................................19
實驗結果...........................................24
討論...............................................33
參考文獻...........................................40
圖表...............................................50
附錄...............................................71

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