β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network.
β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network.
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DOI：
10.1186/s40478-014-0145-3
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发表时间：
2014-09-25
影响因子：
7.1
通讯作者：
Brugg B
中科院分区：
文献类型：
--
作者：
Deleglise B;Magnifico S;Duplus E;Vaur P;Soubeyre V;Belle M;Vignes M;Viovy JL;Jacotot E;Peyrin JM;Brugg B
最近的组织病理学研究表明，阿尔茨海默病和帕金森病的神经退行性过程沿着神经元网络发展，并且标志可以通过神经元通路跨突触传播。潜在的分子机制仍然是未知的，研究一直受到大脑连接的复杂性和实验模型的需要，允许在亚细胞水平上的局部微环境的精细操作的阻碍。在这项研究中，我们在微流控（μFD）装置中培养了原代小鼠皮层神经元，以在流体隔离的微环境中将索马与轴突投射分离，并将β-淀粉样蛋白（Aβ）肽局部应用于不同的细胞区室。我们观察到，Aβ应用于体细胞-树突隔室会触发“回退”过程，涉及半胱天冬酶和NAD+信号通路，而轴突/远端隔室暴露于Aβ沉积物不会诱导轴突变性。相反，与体细胞亚毒性谷氨酸和轴突Aβ肽共同处理引发轴突变性。为了在网络水平上研究这种亚细胞/局部Aβ应激的后果，我们开发了新的μFD多室装置，该装置包含漏斗形微通道，该通道迫使轴突单向生长，并使用它们在体外重建定向的皮质-海马通路。Aβ应用于皮质体-树突室导致快速的皮质突触前损失。这与突触后海马tau蛋白磷酸化同时发生，这可以在轴突和体细胞-树突皮质改变的任何迹象之前被NMDA受体拮抗剂MK-801阻止。由于基于μ FD的重建神经元网络，我们评估了局部Aβ应激对神经元亚室和网络的远距离影响。我们的数据表明，远端神经传递修饰积极参与导致病理进展的异常机制的早期步骤，独立于局部Aβ的产生。这为破译布拉克分期的机制提供了新的工具。我们的数据表明，局部Aβ可以通过远端神经传递障碍在远端tau蛋白病中发挥作用，提供了一个潜在的时空出现的pretangles的假定机制。本文的在线版本（doi：10.1186/s40478-014-0145-3）包含补充材料，可供授权用户使用。
Recent histopathological studies have shown that neurodegenerative processes in Alzheimer’s and Parkinson’s Disease develop along neuronal networks and that hallmarks could propagate trans-synaptically through neuronal pathways. The underlying molecular mechanisms are still unknown, and investigations have been impeded by the complexity of brain connectivity and the need for experimental models allowing a fine manipulation of the local microenvironment at the subcellular level. In this study, we have grown primary cortical mouse neurons in microfluidic (μFD) devices to separate soma from axonal projections in fluidically isolated microenvironments, and applied β-amyloid (Aβ) peptides locally to the different cellular compartments. We observed that Aβ application to the somato-dendritic compartment triggers a “dying-back” process, involving caspase and NAD+ signalling pathways, whereas exposure of the axonal/distal compartment to Aβ deposits did not induce axonal degeneration. In contrast, co-treatment with somatic sub-toxic glutamate and axonal Aβ peptide triggered axonal degeneration. To study the consequences of such subcellular/local Aβ stress at the network level we developed new μFD multi-chamber devices containing funnel-shaped micro-channels which force unidirectional axon growth and used them to recreate in vitro an oriented cortico-hippocampal pathway. Aβ application to the cortical somato-dendritic chamber leads to a rapid cortical pre-synaptic loss. This happens concomitantly with a post-synaptic hippocampal tau-phosphorylation which could be prevented by the NMDA-receptor antagonist, MK-801, before any sign of axonal and somato-dendritic cortical alteration. Thanks to μFD-based reconstructed neuronal networks we evaluated the distant effects of local Aβ stress on neuronal subcompartments and networks. Our data indicates that distant neurotransmission modifications actively take part in the early steps of the abnormal mechanisms leading to pathology progression independently of local Aβ production. This offers new tools to decipher mechanisms underlying Braak's staging. Our data suggests that local Aβ can play a role in remote tauopathy by distant disturbance of neurotransmission, providing a putative mechanism underlying the spatiotemporal appearance of pretangles. The online version of this article (doi:10.1186/s40478-014-0145-3) contains supplementary material, which is available to authorized users.
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影响因子：
25
作者：
Palop, Jorge J.;Mucke, Lennart
通讯作者：
Mucke, Lennart
影响因子：
4.2
作者：
Kabogo, D.;Rauw, G.;Kar, S.
通讯作者：
Kar, S.
影响因子：
16.2
作者：
Mairet-Coello G;Courchet J;Pieraut S;Courchet V;Maximov A;Polleux F
通讯作者：
Polleux F
DOI：
10.3233/jad-2009-1069
发表时间：
2009
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Liang Z;Liu F;Iqbal K;Grundke-Iqbal I;Gong CX
通讯作者：
Gong CX
影响因子：
3.7
作者：
Deleglise B;Lassus B;Soubeyre V;Alleaume-Butaux A;Hjorth JJ;Vignes M;Schneider B;Brugg B;Viovy JL;Peyrin JM
通讯作者：
Peyrin JM