Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
复制标题
淀粉样β寡聚体通过突触前消耗磷脂酰肌醇-4,5-二磷酸抑制兴奋性递质释放
DOI：
10.1038/s41467-019-09114-z
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发表时间：
2019-03-13
影响因子：
16.6
通讯作者：
Zhou, Yu-Dong
中科院分区：
文献类型：
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作者：
He, Yang;Wei, Mengdi;Zhou, Yu-Dong
淀粉样蛋白β (A β)寡聚物诱导的异常神经递质释放被认为是导致阿尔茨海默病（AD）突触功能障碍的关键早期事件。在本研究中，我们报道了在A β产生升高的AD小鼠模型的早期阶段，Schaffer侧枝（SC）和CA1锥体神经元之间突触的释放概率（Pr）显着降低。高纳摩尔合成低聚物A β(42)也抑制野生型小鼠SC-CA1突触的Pr。这种an诱导的Pr抑制主要是由于mglur5介导的轴突中磷脂酰肌醇4,5-二磷酸（PIP2）的损耗。选择性抑制海马CA3区A β诱导的PIP2水解，强烈阻止A β诱导的SC-CA1突触Pr的抑制，并挽救APP/PS1小鼠的突触和空间学习和记忆缺陷。这些结果首次揭示了突触前mGluR5-PIP2途径，寡聚物A β在AD中诱导早期突触缺陷。
Amyloid beta (A beta) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated A beta production. High nanomolar synthetic oligomeric A beta(42) also suppresses Pr at the SC-CA1 synapse in wild-type mice. This An-induced suppression of Pr is mainly due to an mGluR5-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PIP2) in axons. Selectively inhibiting A beta-induced PIP2 hydrolysis in the CA3 region of the hippocampus strongly prevents oligomeric A beta-induced suppression of Pr at the SC-CA1 synapse and rescues synaptic and spatial learning and memory deficits in APP/PS1 mice. These results first reveal the presynaptic mGluR5-PIP2 pathway whereby oligomeric A beta induces early synaptic deficits in AD.