Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer's disease immunotherapeutics.
Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer's disease immunotherapeutics.
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针对适当的淀粉样β神经元毒素：阿尔茨海默病免疫治疗的前进之路。
DOI：
10.1186/alzrt272
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Hefti F
中科院分区：
文献类型：
--
作者：
Goure WF;Krafft GA;Jerecic J;Hefti F
阿尔茨海默病患者大脑中淀粉样β单体和沉积的淀粉样β蛋白的水平比可溶性淀粉样β蛋白寡聚体的水平高出几个数量级。单体淀粉样β蛋白没有已知的直接毒性。不溶性纤维淀粉样β蛋白已被认为是体内清除可溶性淀粉样蛋白β的机制，并且表现出相对较低的毒性。相比之下，可溶性淀粉样β蛋白寡聚体被广泛报道为毒性最大的淀粉样β蛋白形式，既会引起急性突触毒性，又会引发神经变性过程。目前正在临床开发的淀粉样β蛋白免疫疗法中没有一种是选择性地针对可溶性淀粉样β寡聚体的，考虑到它们对单体或纤维样β淀粉样蛋白(或两者)的选择性，而不是可溶性淀粉样β寡聚体，它们缺乏疗效也就不足为奇了。由于它们表现出急性的、损害记忆的突触毒性和诱导慢性神经退行性毒性，而且因为它们在阿尔茨海默病的大脑中存在于体内非常低的水平，所以可溶性淀粉样β寡聚体构成了应该更积极地追求的最佳免疫治疗靶点。
Levels of amyloid-beta monomer and deposited amyloid-beta in the Alzheimer’s disease brain are orders of magnitude greater than soluble amyloid-beta oligomer levels. Monomeric amyloid-beta has no known direct toxicity. Insoluble fibrillar amyloid-beta has been proposed to be an in vivo mechanism for removal of soluble amyloid-beta and exhibits relatively low toxicity. In contrast, soluble amyloid-beta oligomers are widely reported to be the most toxic amyloid-beta form, both causing acute synaptotoxicity and inducing neurodegenerative processes. None of the amyloid-beta immunotherapies currently in clinical development selectively target soluble amyloid-beta oligomers, and their lack of efficacy is not unexpected considering their selectivity for monomeric or fibrillar amyloid-beta (or both) rather than soluble amyloid-beta oligomers. Because they exhibit acute, memory-compromising synaptic toxicity and induce chronic neurodegenerative toxicity and because they exist at very low in vivo levels in the Alzheimer’s disease brain, soluble amyloid-beta oligomers constitute an optimal immunotherapeutic target that should be pursued more aggressively.
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影响因子：
4
作者：
Bohrmann, Bernd;Baumann, Karlheinz;Loetscher, Hansruedi
通讯作者：
Loetscher, Hansruedi
DOI：
10.1124/jpet.104.075408
发表时间：
2005-02-01
影响因子：
3.5
作者：
Barten, DM;Guss, VL;Felsenstein, KM
通讯作者：
Felsenstein, KM
DOI：
10.1093/protein/11.9.761
发表时间：
1998-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Chaney, MO;Webster, SD;Roher, AE
通讯作者：
Roher, AE
影响因子：
5.5
作者：
Bitan, G;Fradinger, EA;Teplow, DB
通讯作者：
Teplow, DB
影响因子：
5.3
作者：
Adolfsson, Oskar;Pihlgren, Maria;Watts, Ryan J.
通讯作者：
Watts, Ryan J.