Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function.
Neurotoxic effects induced by the Drosophila amyloid-beta peptide suggest a conserved toxic function.
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DOI：
10.1016/j.nbd.2008.10.014
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发表时间：
2009-02
影响因子：
6.1
通讯作者：
Kretzschmar D
中科院分区：
文献类型：
--
作者：
Carmine-Simmen K;Proctor T;Tschäpe J;Poeck B;Triphan T;Strauss R;Kretzschmar D
淀粉样蛋白-β（Aβ）积聚成斑块是阿尔茨海默病（AD）的标志性特征。虽然淀粉样前体蛋白（APP）相关蛋白存在于大多数生物体中，但只有来自人类APP的Aβ片段显示可诱导淀粉样蛋白沉积和进行性神经变性。因此，有人认为神经毒性作用是人Aβ的一种特异性。在这里，我们表明，Aβ片段来自果蝇直系同源APPL聚集成细胞内纤维，淀粉样蛋白沉积，并导致年龄依赖性行为缺陷和神经退行性变。我们还发现APPL可以被一种新的苍蝇β-分泌酶样酶切割。这表明Aβ诱导的神经毒性是APP蛋白的保守功能，因此一级序列中缺乏保守性表明二级结构方面决定了其发病机制。此外，我们发现行为表型先于细胞外淀粉样蛋白存款形成，支持细胞内Aβ在AD中起关键作用的结果。
The accumulation of amyloid-β (Aβ) into plaques is a hallmark feature of Alzheimer's disease (AD). While amyloid precursor protein (APP)-related proteins are found in most organisms, only Aβ fragments from human APP have been shown to induce amyloid deposits and progressive neurodegeneration. Therefore, it was suggested that neurotoxic effects are a specific property of human Aβ. Here we show that Aβ fragments derived from the Drosophila orthologue APPL aggregate into intracellular fibrils, amyloid deposits, and cause age-dependent behavioral deficits and neurodegeneration. We also show that APPL can be cleaved by a novel fly β-secretase-like enzyme. This suggests that Aβ-induced neurotoxicity is a conserved function of APP proteins whereby the lack of conservation in the primary sequence indicates that secondary structural aspects determine their pathogenesis. In addition, we found that the behavioral phenotypes precede extracellular amyloid deposit formation, supporting results that intracellular Aβ plays a key role in AD.
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影响因子：
64.8
作者：
LEVITAN, D;GREENWALD, I
通讯作者：
GREENWALD, I
影响因子：
5.3
作者：
LUO, LQ;MARTINMORRIS, LE;WHITE, K
通讯作者：
WHITE, K
DOI：
10.1073/pnas.90.24.12045
发表时间：
1993-12-15
影响因子：
11.1
作者：
DAIGLE, I;LI, C
通讯作者：
LI, C
影响因子：
6.2
作者：
Kretzschmar, D;Tschäpe, J;Pflugfelder, GO
通讯作者：
Pflugfelder, GO
DOI：
10.1073/pnas.58.3.1112
发表时间：
1967-01-01
影响因子：
11.1
作者：
BENZER, S
通讯作者：
BENZER, S