新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 帕金森病 » Nature:科学家构建人类阿尔兹海默症神经细胞3D模型

Nature:科学家构建人类阿尔兹海默症神经细胞3D模型

来源:生物谷 2014-10-20 15:45

2014年10月20日讯 /生物谷BIOON/ --近年来,随着生物技术的高速发展,癌症等以往被视为绝症的疾病正在逐步取得重大进展。然而,以阿尔兹海默病等为代表的神经退行性疾病的研究却仍未能够取得重大进展。这其中一个重要原因就是研究人员始终未能彻底了解淀粉样蛋白体在这些疾病中作用的机制。

据统计,有99.6%的阿尔兹海默症候选药物最终都失败,如此高的失败概率也使得各大生物制药公司对这一领域讳莫如深。

最近来自 Massachusetts General Hospital的研究人员在国际著名杂志Nature上发表了他们的研究结果,有望助阿尔兹海默症等疾病研究走出困境。在这项研究中,科学家们成功构建体外阿尔兹海默症疾病模型,这使得科研人员在体外观察大脑神经元中淀粉样蛋白体的积聚以及淀粉样蛋白体对神经元的毒害作用成为可能。可以说这一模型有望将阿尔兹海默症的整个发病过程直接展现在科学家眼前。

这项研究的作者Rudy Tanzi和Doo Yeon Kim主要是通过在凝胶介质的培养基中培养神经元细胞,从而构建了一个3D模型。而这些神经元中带有淀粉样前体蛋白和另一种与阿尔兹海默症相关的蛋白前体基因presenilin 1突变型。经过六周的培养,研究人员成功在这一模型中观测到明显的淀粉样蛋白体积聚直至导致神经元死亡。另一方面,研究人员也在这一过程中确定了对神经元凋亡起到重要作用的酶--GSK3-beta。当GSK3-beta被阻断时,淀粉样蛋白的产生受到明显抑制。科学家认为这表明GSK3-beta有希望成为治疗阿尔兹海默症的一个潜在分子靶点。

相对于过去的小鼠模型,这一新型体外模型能够更好地展现大脑神经元发生病变的更多细节。这一研究也将对今后的阿尔兹海默症研究产生积极的影响。(生物谷Bioon.com)

本文系生物谷原创编译整理,欢迎转载!转载请注明来源并附原文链接。谢谢!

生物谷推荐的英文摘要:

Nature   doi:10.1038/nature13800

A three-dimensional human neural cell culture model of Alzheimer’s disease

Se Hoon Choi, Young Hye Kim, Matthias Hebisch, Christopher Sliwinski, Seungkyu Lee, Carla D’Avanzo, Hechao Chen, Basavaraj Hooli, Caroline Asselin, Julien Muffat, Justin B. Klee, Can Zhang, Brian J. Wainger, Michael Peitz, Dora M. Kovacs, Clifford J. Woolf, Steven L. Wagner, Rudolph E. Tanzi & Doo Yeon Kim

Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles1. The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau2, 3. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology4, 5. Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles6, 7, 8, 9, 10, 11. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库