Identifying Aβ-specific pathogenic mechanisms using a nematode model of Alzheimer's disease.
Identifying Aβ-specific pathogenic mechanisms using a nematode model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2014.10.016
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发表时间：
2015-02
影响因子：
4.2
通讯作者：
Link CD
中科院分区：
文献类型：
--
作者：
Hassan WM;Dostal V;Huemann BN;Yerg JE;Link CD
阿尔茨海默病（AD）与多种基因表达改变有关，其发病机制涉及多种代谢途径。然而，AD特异性基因表达变化和对毒性聚集蛋白的非特异性反应引起的基因表达变化之间的区别还没有明确。我们在秀丽隐杆线虫阿尔茨海默病模型中研究了人类β-淀粉样肽（Aβ）诱导的基因表达的改变。将Aβ诱导的基因表达变化与合成聚集蛋白引起的基因表达变化进行比较，以确定Aβ特异性效应。观察到Aβ特异性和非特异性改变。在Aβ特异性基因中，有那些与衰老、蛋白酶体功能和线粒体功能有关的基因。一个有趣的观察结果是Aβ诱导的基因表达变化与细菌成孔毒素Cry 5 B诱导的基因表达变化之间的显著重叠。这使我们假设Aβ发挥其毒性作用，至少部分是通过对生物膜造成损伤。我们提供了与这一假设一致的体内证据。本研究区分了Aβ特异性和非特异性机制，并为治疗药物的发现提供了潜在的靶点。
Multiple gene expression alterations have been linked to Alzheimer’s disease (AD), implicating multiple metabolic pathways in its pathogenesis. However, a clear distinction between AD-specific gene expression changes and those resulting from non-specific responses to toxic aggregating proteins has not been made. We investigated alterations in gene expression induced by human β-amyloid peptide (Aβ) in a Caenorhabditis elegans Alzheimer’s disease model. Aβ-induced gene expression alterations were compared to those caused by a synthetic aggregating protein to identify Aβ-specific effects. Both Aβ-specific and non-specific alterations were observed. Among Aβ-specific genes were those involved in aging, proteasome function, and mitochondrial function. An intriguing observation was the significant overlap between gene expression changes induced by Aβ and those induced by Cry5B, a bacterial pore-forming toxin. This led us to hypothesize that Aβ exerts its toxic effect, at least in part, by causing damage to biological membranes. We provide in vivo evidence consistent with this hypothesis. This study distinguishes between Aβ-specific and non-specific mechanisms and provides potential targets for therapeutics discovery.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
30.3
作者：
Los FC;Kao CY;Smitham J;McDonald KL;Ha C;Peixoto CA;Aroian RV
通讯作者：
Aroian RV
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
9.8
作者：
Heller K
通讯作者：
Heller K
影响因子：
3
作者：
Ferrer, Isidre
通讯作者：
Ferrer, Isidre