Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake.
Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake.
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DOI：
10.1016/j.neuron.2009.05.012
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发表时间：
2009-06-25
期刊：
影响因子：
16.2
通讯作者：
Selkoe, Dennis
中科院分区：
文献类型：
--
作者：
Li, Shaomin;Hong, Soyon;Shepardson, Nina E.;Walsh, Dominic M.;Shankar, Ganesh M.;Selkoe, Dennis
在阿尔茨海默病（AD）中，陈述性记忆的潜在损害与细胞外淀粉样β蛋白（Aβ）和神经元内tau聚集体的积累相一致。痴呆症的严重程度与海马和皮质中突触密度的降低密切相关。尽管大量研究表明可溶性Aβ寡聚体抑制海马长时程增强，但其在长时程突触抑制（LTD）中的作用仍不清楚。在这里，我们报告了几种来源（合成、细胞培养、人脑提取物）的可溶性Aβ寡聚体促进了CA 1区的电诱发LTD。Aβ增强的LTD由mGluR或NMDAR活性介导，这取决于诱导方案。这两种形式的LTD的细胞外谷氨酸清除剂系统防止。谷氨酸再摄取抑制剂TBOA的作用与Aβ促进的LTD密切相关，包括对细胞外钙水平的共同依赖性以及PP 2B和GSK-3信号的激活。与此雅阁，可溶性Aβ显著降低突触谷氨酸摄取。我们得出结论，可溶性Aβ寡聚体通过改变突触处的谷氨酸再循环和促进突触抑制来扰乱突触可塑性。
In Alzheimer's disease (AD), the insidious impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically-evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity, depending on the induction protocol. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was closely mimicked by the action of the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.
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影响因子：
3.4
作者：
Harkany, T;Abrahám, I;Luiten, PGM
通讯作者：
Luiten, PGM
影响因子：
3.3
作者：
Gu, QB;Zhao, JX;Schwarz, W
通讯作者：
Schwarz, W
影响因子：
3.3
作者：
Campbell, SL;Hablitz, JJ
通讯作者：
Hablitz, JJ
影响因子：
4.2
作者：
Dewachter, I.;Filipkowski, R. K.;Van Leuven, F.
通讯作者：
Van Leuven, F.
DOI：
10.1073/pnas.96.6.3228
发表时间：
1999-03-16
影响因子：
11.1
作者：
Hsia, AY;Masliah, E;Mucke, L
通讯作者：
Mucke, L