環境因子與Abeta1-40加成性傷害空間學習及記憶行為

The synergistic effects of environmental factors and Abeta1-40 impaired the spatial learning and memory in mice

黃慧貞(Hei-Jen Huang)

指導教授 ： 謝秀梅

國立臺灣師範大學/理學院/生命科學研究所/博士(2010年)

摘要

阿茲海默氏症(Alzheimer's Disease)於中樞神經系統內主要病變特徵之一為澱粉樣斑塊堆積。Aβ蛋白質（長約39到43個胺基酸）是穿膜本體蛋白質β-amyloid precursor protein (APP)的代謝物，是造成澱粉樣斑塊最主要之原因；大部分Aβ蛋白質為Aβ1-40與Aβ1-42。雖然Aβ1-42於澱粉樣斑塊及認知功能受損中扮演著舉足輕重的角色，但是在阿茲海默氏症早期階段時Aβ1-40的分泌量遠超過Aβ1-42；甚至有研究發現Aβ1-40在阿茲海默氏症晚期階段病因形成有所相關。因此本論文主要探討環境因子是否會提升Aβ1-40的毒性及如何造成神經退化之機轉。首先，第一個實驗所運用的環境因子為第I型糖尿病所造成的高血糖與Aβ1-40交互作用所產生的影響。結果發現，單獨高血糖或Aβ1-40都無法造成海馬回顯著性地神經退化及空間學習及記憶之損壞；但是高血糖同時併入Aβ1-40會造成Aβ1-40大量堆積、氧化壓力增加及細胞凋亡，最後導致空間學習及記憶之受損。第二個實驗主要探討老化(aged)與Aβ1-40之間的關係，所使用的老鼠為阿茲海默氏症雙基因 (APP/PS1) 突變的背景鼠種(C57BL/6J × C3H)。雖然不論何種阿茲海默氏症基因轉殖鼠均無法完全模擬人類罹患阿茲海默氏症，然而不同鼠種背景之阿茲海默氏症基因轉殖鼠其致病原因及行為受損程度卻有所差異。因為我們實驗室APP/PS1雙基因突變的基因轉殖鼠其背景鼠種為(C57BL/6J × C3H)，所以此實驗對象為C57BL/6J (母) 與 C3H (公) 交配所產生的第一子代公鼠。結果發現，老化與Aβ1-40交互作用會產生短暫性體重下降及空間記憶提取之問題；所以推測體重短暫性下降或許是老年癡呆症的早期訊號。最後一個實驗探討之環境因子是目前時下許多人所面臨之狀況—壓力，觀察壓力與Aβ1-40之間的交互作用；結果發現海馬回處出現細胞凋亡及突觸功能受損而導致嚴重的空間學習及記憶之受損。綜合以上的結果，發現Aβ1-40的毒性會受到環境因子之影響而提升而且不論哪一種環境因子與Aβ1-40相互作用都是透過氧化壓力之傷害，因此建議抗氧化壓力之治療或預防措施能延緩阿茲海默氏症病程之發展。

關鍵字

阿茲海默氏症 ； 壓力 ； 老化 ； 高血糖 ； 抗氧化治療 ； Aβ1-40蛋白質

並列摘要

The deposition of beta amyloid (Aβ) as soluble or insoluble aggregates in senile plaques has been well characterized in the Alzheimer’s disease (AD) brain. Aβ peptides are composed of 39-43 amino acids derived from the soluble metabolic products of amyloid beta precursor protein (APP). Most of the soluble Aβ species comprise the species Aβ1-40 and Aβ1-42. Many studies focus on the Aβ1-42, which plays an important role in plaques and behavioral deficits in the AD. However, Aβ1-40 receives more attention in recent AD studies. A higher proportion of Aβ1-40 is present in the brain under the general condition, an increase of Aβ1-40 / Aβ1-42 ratio in cerebrospinal fluid was identified at the early stage of AD, and an important role of Aβ1-40 was identified in the pathogenesis of late-onset sporadic AD. Therefore, this dissertation worked on characterization of the effects of the interaction between environmental factors and Aβ1-40. First, we found that the neurotoxicity of Aβ1-40 could be enhanced by hyperglycemia, that enhanced the AD symptoms through the oxidative stress caused by Aβ accumulation. Second, the interaction between Aβ1-40 infusion and aged not only caused transient body-weight loss but also impaired the retrieval of spatial reference memory in the C57BL/6J × C3H hybrid mice which have been used as the common AD transgenic model, the APP/PS1 double mutant mice. Therefore, transient body-weight loss may be an important sign of early dementia with aging. Finally, the combined treatment of the stress and oligomer Aβ1-40 induced severe impairment of spatial learning and memory through apoptosis and synaptic dysfunction in the hippocampus. The above results, we suggested that the interaction between Aβ1-40 and environmental factors induced the cognitive dysfunction through the oxidative stress. Therefore, the antioxidant therapy may be a potential strategy to delay the onset of these devastating pathologies.

並列關鍵字

Alzheimer’s disease ； stress ； aging ； hyperglycemia ； antioxidant therapy ； Aβ1-40

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