Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors.
Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors.
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DOI：
10.1523/jneurosci.0203-11.2011
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发表时间：
2011-05-04
期刊：
影响因子：
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通讯作者：
Selkoe DJ
中科院分区：
文献类型：
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作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
在阿尔茨海默病中，痴呆的严重程度与海马和皮质中突触密度的降低密切相关。大量研究表明，可溶性β淀粉样蛋白（amyloid β-protein，Aβ）寡聚体可抑制海马LTP，但介导这种作用的突触元件尚不清楚。我们研究了野生型小鼠海马脑片的场兴奋性突触后电位和全细胞记录。来自三种不同来源（培养细胞、AD皮质或合成肽）的可溶性Aβ寡聚体抑制LTP，选择性NR 2B抑制剂艾芬地尔和Ro 25-6981可阻止这种抑制。可溶性Aβ增强NR 2B介导的NMDA电流和突触外反应;谷氨酸再摄取抑制剂TBOA模拟了这些作用。下游，Aβ介导的p38 MAPK激活的升高随后是CREB蛋白的下调，并且通过p38 MAPK或钙蛋白酶的抑制剂防止LTP损伤。因此，AD脑中存在的低纳摩尔水平的可溶性Aβ寡聚体增加了突触外含NR 2B受体的激活，从而损害了突触可塑性。
In Alzheimer's disease, dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal LTP can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field excitatory postsynaptic potentials and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors, Ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor, TBOA. Downsteam, an Aβ-mediated rise in p38 MAPK activation was followed by downregulation of CREB protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.