Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5.
Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5.
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DOI：
10.1016/j.neuron.2010.04.029
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发表时间：
2010-06-10
期刊：
影响因子：
16.2
通讯作者：
Triller, Antoine
中科院分区：
文献类型：
--
作者：
Renner, Marianne;Lacor, Pascale N.;Velasco, Pauline T.;Xu, Jian;Contractor, Anis;Klein, William L.;Triller, Antoine
淀粉样蛋白β (a β)的可溶性低聚物在阿尔茨海默病的记忆障碍特征中发挥作用。作为致病性配体，Aβ低聚物结合到特定的突触并扰乱其功能，形态和维持。通过量子点标记的低聚物和突触蛋白的单粒子跟踪，研究了活海马神经元中低聚物结合后不久发生的事件。膜附着的低聚物最初自由移动，但在突触积累时，它们的扩散受到明显阻碍。同时，个体代谢性谷氨酸受体（mGluR5）表现出显著减少的横向扩散，因为它们变得异常聚集。这种mGluR5的聚集会升高细胞内钙并导致突触恶化，而mGluR5拮抗剂可以阻止这种反应。正如预期的那样，人工交联的聚类也促进了突触毒性。这些结果揭示了a β低聚物诱导谷氨酸受体异常积累和过度稳定的机制，从而为a β低聚物诱导早期突触失效提供了机制和分子基础。
Soluble oligomers of amyloid β (Aβ) play a role in the memory impairment characteristic of Alzheimer’s disease. Acting as pathogenic ligands, Aβ oligomers bind to particular synapses and perturb their function, morphology, and maintenance. Events that occur shortly after oligomer binding have been investigated here in live hippocampal neurons by single particle tracking of quantum dot-labeled oligomers and synaptic proteins. Membrane-attached oligomers initially move freely, but their diffusion is hindered markedly upon accumulation at synapses. Concomitantly, individual metabotropic glutamate receptors (mGluR5) manifest strikingly reduced lateral diffusion as they become aberrantly clustered. This clustering of mGluR5 elevates intracellular calcium and causes synapse deterioration, responses prevented by an mGluR5 antagonist. As expected, clustering by artificial crosslinking also promotes synaptotoxicity. These results reveal a mechanism whereby Aβ oligomers induce the abnormal accumulation and overstabilization of a glutamate receptor, thus providing a mechanistic and molecular basis for Aβ oligomer-induced early synaptic failure.
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影响因子：
4.7
作者：
Husi, H;Grant, SGN
通讯作者：
Grant, SGN
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
DOI：
10.1098/rstb.2005.1766
发表时间：
2005-12-29
影响因子：
6.3
作者：
Abramov, AY;Duchen, MR
通讯作者：
Duchen, MR
DOI：
10.1196/annals.1441.015
发表时间：
2008-01-01
期刊：
ADDICTION REVIEWS 2008
影响因子：
--
作者：
Carroll, F. Ivy
通讯作者：
Carroll, F. Ivy
影响因子：
2.9
作者：
Chromy, BA;Nowak, RJ;Klein, WL
通讯作者：
Klein, WL