Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss.
Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss.
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DOI：
10.1038/cddis.2015.160
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发表时间：
2015-06-18
影响因子：
9
通讯作者：
Tackenberg C
中科院分区：
文献类型：
--
作者：
Birnbaum JH;Bali J;Rajendran L;Nitsch RM;Tackenberg C
突触丢失是阿尔茨海默病(AD)的主要特征之一，与痴呆程度相关。N-甲基-d-天冬氨酸受体(NMDAR)在AD模型中介导β-淀粉样多肽(A-β)的下游效应。NMDAR可以通过钙离子内流触发细胞内的级联反应，然而，也描述了NMDARs的钙非依赖性(代谢性)功能。我们的目的是确定Aβ诱导突触丢失是否需要电离型或代谢型NMDAR信号。我们发现内源性Aβ以及外源性添加的合成Aβ寡聚体诱导了海马片培养中树突棘的丢失以及突触前和突触后蛋白水平的降低。用NMDAR拮抗剂APV阻断谷氨酸与NMDAR的结合可减轻突触改变，但不能用钙离子螯合剂BAPTA或开放通道阻滞剂MK-801或美金刚阻止离子流动。β可增加p38MAPK的活性，p38MAPK是一种参与长期抑制的激酶，抑制p38MAPK可消除树突棘的丢失。β诱导的p38MAPK活性的增加可被APV阻止，但不能被BAPTA、MK-801或美金刚阻止，强调了谷氨酸与NMDAR结合的作用，但不能阻止Ca~(2+)通量在Aβ导致突触变性中的作用。我们进一步表明，用G蛋白抑制剂百日咳毒素(Ptx)治疗并不能防止在Aβ寡聚体存在的情况下树突棘的丢失。我们的数据表明，Aβ通过钙离子通量和G蛋白非依赖的机制诱导p38MAPK的激活和随后的突触丢失。
Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-d-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca2+ entry, however, also Ca2+-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca2+ chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca2+ flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca2+ flux- and G protein-independent mechanisms.