The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice
The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice
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DOI：
10.1016/j.neurobiolaging.2004.12.007
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发表时间：
2006-01-01
影响因子：
4.2
通讯作者：
Nilsson, LNG
中科院分区：
文献类型：
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作者：
Lord, A;Kalimo, H;Nilsson, LNG
北极突变 (APP E693G) 是独特的，因为它位于淀粉样蛋白 - β (A beta) 序列内并导致阿尔茨海默病 (AD)。 Arctic Aβ肽在体外更容易形成Aβ原纤维，但对Arctic突变在体内的致病机制知之甚少。在这里，我们分析了同时具有瑞典和北极突变的 APP 转基因小鼠 (tg-APP(ArcSwe)) 和仅具有瑞典突变的转基因小鼠 (tg-APP(Swe))。年轻的 tg-APP(ArcSwe) 小鼠中存在强烈的神经元内 A β-免疫反应性染色，但 tg-APP(Swe) 小鼠中不存在。 tg-APP(ArcSwe) 中的细胞内 Aβ 聚集体被识别 Aβ N 末端的抗体强烈染色，而识别 Aβ C 末端的抗体染色较弱。在 tg-APP(ArcSwe) 和 tg-APP(Swe) 小鼠中，神经元内的 Aβ 聚集随着年龄的增长而增加，并且细胞外 Aβ 沉积提前。与 tg-APP(Swe) 小鼠相比，tg-APP(ArcSwe) 小鼠的老年斑沉积明显加速。我们得出的结论是，北极突变通过细胞内 Aβ 聚集物的早期积累促进淀粉样变性，并与老年斑沉积的快速发生相关，从而导致 AD。 (C) 2005 Elsevier Inc. 保留所有权利。
The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (A beta) sequence and leads to Alzheimer's disease (AD). Arctic A beta peptides more easily form A beta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APP(ArcSwe)) and transgenic mice with the Swedish mutation alone (tg-APP(Swe)). Intense intraneuronal A beta-immunoreactive staining was present in young tg-APP(ArcSwe) mice, but not in tg-APP(Swe) mice. Intracellular A beta aggregates in tg-APP(ArcSwe) were strongly stained by antibodies recognizing the N-terminus of A beta, while those recognizing the C-terminus of A beta stained weakly. The A beta aggregates inside neurons increased with age and predated extracellular A beta deposition in both tg-APP(ArcSwe) and tg-APP(Swe) mice. Senile plaque deposition was markedly accelerated in tg-APP(ArcSwe) mice, as compared to tg-APP(Swe) mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular A beta aggregates in association with a rapid onset of senile plaque deposition. (C) 2005 Elsevier Inc. All rights reserved.