臺灣博碩士論文加值系統

阿茲海默症(Alzheimer’s disease，AD)是目前最常發現在老年的失智症(dementia)，不過百分之九十五的患者為非家族性遺傳而是突發性、晚發型患者，其病因至今尚未明瞭。研究文獻指出senile plaque形成之前就已存在Abeta oligomer，其電生理功能是降低海馬廻LTP，動物行為學測試上會降低小鼠的學習與記憶。因為有研究指出若在帶有prion的轉殖基因小鼠其周邊造成發炎反應，會進一步使prion引起的神經退化性疾病加速惡化，所以我的研究假說是生物體周邊的發炎反應會加速AD的Abeta oligomer及plaque形成，我們使用6.5月大APP/PS1轉殖基因小鼠，於plaque才剛開始在腦部出現時，開始進行腹腔注射1.5 mg/kg LPS引發周邊發炎，藉此研究慢性周邊發炎與Abeta oligomer及plaque的關係。施打LPS結束後將小鼠進行學習與記憶相關的水迷宮測試，測試結束後將對照組與LPS組的部份小鼠犧牲，進行Thioflavin-S染色plaque的實驗，發現所用的轉殖基因小鼠腦部幾乎沒有斑塊。其餘小鼠接下來再進行fear contextual test。在Morris water maze test和fear contextual test等學習與記憶相關行為學測試中，cue reference memory version of the Morris water maze test中，LPS組轉殖基因小鼠較saline組轉殖基因小鼠逃離水面的時間較長，另外在fear contextual test的實驗，LPS組轉殖基因小鼠較saline組轉殖基因小鼠freezing百分比低，這些都建議在周邊施打LPS可能使APP/PS1轉殖基因小鼠其acquisition learning deficit。因saline組與1.5 mg/kg LPS組Thioflavin-S染色plaque的結果沒有明顯差異因此在小鼠約11月大時，腹腔再注射一次5mg/kg LPS，約12月大時才將小鼠犧牲。犧牲後的小鼠腦切片，利用Thioflavin-S與BSB染色來觀察plaque。因Thioflavin-S與BSB所染到的plaque外形皆相類似，再加上兩組小鼠中只有二到三隻小鼠的腦切片可藉由Thioflavin-S或BSB染到plaque，所以saline組與LPS組APP/PS1轉殖基因小鼠腦中出現的plaque數量大小本組間差異極大，動物隻數不夠多，因此無法就plaque面積與plaque數目進一步做統計分析。

Alzheimer's disease (AD) is the most common form of dementia in the aged persons. 5% of AD patients are familial heredity, other 95% of AD patients are sporadic, the late-onset case. The etiology of AD remains unclear. Oligomeric Abeta (oAbeta) appears prior to the senile plaque. The electricity physiological studies show that the long-term potentiation (LTP) of the hippocampus is reduced. The behavior studies show that the learning and memories in the presence of oAbeta reduced. It is shown that the peripheral inflammation on the prion transgenic mice will further deteriorate the prion-induced neurodegeneration. Therefore, my research hypothesis is that peripheral inflammation will accelerate the appearance of oAbeta during the pathology of AD. Based on the characterization of APP/PS1 double transgenic mice published in the literature, the minor Abeta plaque appears at 6.5 months. The systemic inflammation is induced in intraperitoneal injection 1.5 mg/kg LPS into 6.5 months old APP/PS1 transgenic mice. In this thesis, I explored the relationship between the systemic inflammation and the AD pathology development. After 6 weeks LPS injection, these mice were carried out the Morris water maze test. Afterward, some of control and LPS groups partial mice were sacrificed for Abeta senile plaque characterization. The rest mice were carry out the fear contextual test. Using the cue reference memory version of the Morris water maze test, the LPS group has longer latency than the saline group. Moreover, in fear contextual test, the LPS group has lower freezing percentage than the saline group of transgenic mice. It is suggested that peripheral LPS injection in APP/PS1 transgenic mice might cause the acquisition learning deficit. Because the pathological examination did not find any Abeta plaque at 9 month-old transgenic mice. The rest of transgenic mice at 11 months old were injected 5mg/kg LPS and sacrificed in 12 months old. Thioflavin-S and BSB were used to stain the characterization of beta-amyloid plaques. The morphology of beta-amyloid plaque in two groups of mice looks similar. The number of Abeta plaques in the saline group and the LPS group of APP/PS1 transgenic mice vary significantly. Only 3 out of 7 saline group and 2 out of 8 LPS group contain senile plaques. Due to the small number of Abeta plaque-carrying mice, the comparison of the area and number of ��-amyloid plaque in saline and LPS group of APP/PS1 transgenic mice are not further proceeded.

縮寫表…………………………………………. ii
中文摘要…………………………………….. iii
英文摘要................................ iv
前言…………………………………………….. 1
材料與方法…………………………………. 18
結果…………………………………………….. 26
討論…………………………………………….. 34
參考文獻……………………………………… 40
圖表……………………………………………… 54

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