Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures.
Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures.
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DOI：
10.2174/156720512802455322
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发表时间：
2012-08
影响因子：
2.1
通讯作者：
S. Mota;I. Ferreira;C. Pereira;C. Oliveira;A. Rego
中科院分区：
文献类型：
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作者：
S. Mota;I. Ferreira;C. Pereira;C. Oliveira;A. Rego
阿尔茨海默病（AD）是老年人中最常见的与年龄相关的神经退行性疾病。n甲基- d -天冬氨酸受体（NMDAR）过度激活与阿尔茨海默病晚期神经退行性变之前的早期突触功能障碍有关。此外，淀粉样β肽（Aβ） 1-42的低聚物被认为是最具突触毒性的形式，是阿尔茨海默病早期认知缺陷的原因。在这项工作中，我们通过改变成熟海马培养物的微管聚合来评估NMDARs在a β诱发的神经元功能障碍和细胞死亡中的作用。暴露于a β 1-42导致β - iii微管蛋白和聚合α微管蛋白的总水平和聚合水平下降，表明微管解体。此外，Aβ在神经元和非神经元细胞中均可诱导DNA断裂。事实上，Aβ对β - iii微管蛋白聚合的影响与神经突长度减少和神经元DNA断裂显著相关。有趣的是，这些作用被MK-801和美金刚阻止，这表明突触外NMDARs在a β毒性中起作用，而伊芬prodil进一步表明含有glun2b的NMDARs参与其中。然而，暴露于Aβ并没有增强NMDARs选择性激活引起的效应。数据在很大程度上表明，a β诱导的海马神经元功能障碍发生在成熟海马细胞中，与神经突缩回和DNA断裂相关的nmdar依赖的微管解体。
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder among the elderly. Nmethyl- D-aspartate receptor (NMDAR) overactivation has been implicated in early synaptic dysfunction that precedes late neurodegeneration in AD. Moreover, oligomers of amyloid-beta peptide (Aβ) 1-42 are considered the most synaptotoxic forms, responsible for early cognitive deficits in AD. In this work we evaluate the role of NMDARs on Aβ-evoked neuronal dysfunction and cell death through changes in microtubule polymerization in mature hippocampal cultures. Exposure to Aβ 1-42 caused a decrease in total and polymerized levels of beta-III tubulin and polymerized alpha-tubulin, suggesting microtubule disassembly. Moreover, Aβ induced DNA fragmentation in both neuronal and non-neuronal cells. Indeed, the effects of Aβ on beta-III tubulin polymerization were significantly correlated with reduced neurite length and neuronal DNA fragmentation. Interestingly, these effects were prevented by MK-801 and memantine, suggesting a role for extrasynaptic NMDARs in Aβ toxicity, and by ifenprodil, further indicating the involvement of GluN2B-containing NMDARs. Nevertheless, exposure to Aβ did not potentiate the effects caused by selective activation of NMDARs. Data largely suggest that Aβ-induced hippocampal neuronal dysfunction occurs through NMDAR-dependent microtubule disassembly associated to neurite retraction and DNA fragmentation in mature hippocampal cells.