Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization.
Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization.
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DOI：
10.1038/srep42548
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Takahashi H
中科院分区：
文献类型：
--
作者：
Naito Y;Tanabe Y;Lee AK;Hamel E;Takahashi H
阿尔茨海默病（Alzheimer's disease，AD）是一种以β-淀粉样蛋白（amyloid-beta，Aβ）的过度分泌和沉积以及突触功能障碍和丧失为特征的疾病。虽然可溶性Aβ寡聚体（AβOs）对突触功能具有有害影响并减少突触数量，但其潜在的分子机制尚未完全了解。在这里，我们筛选了突触组织蛋白与AβOs的细胞表面相互作用，并确定了神经毒素（NRXs）和AβOs之间的新相互作用。AβOs通过β-NRX 1/2/3的N-末端富组氨酸结构域（HRD）和NRX 1/2剪接位点4处的选择性剪接插入片段与NRXs结合。在人工突触形成试验中，AβOs减少了NRX相互作用蛋白（包括神经连接素1/2（NLG 1/2）和富含亮氨酸的重复跨膜蛋白LRRTM 2）诱导的兴奋性突触前分化。尽管Aβ O不干扰NRX 1 β与NLG 1或LRRTM 2的结合，但延时成像显示AβO处理减少了轴突上NRX 1 β的表面表达，并且这种减少依赖于NRX 1 β HRD。在表达突变的人淀粉样前体蛋白的转基因小鼠中，β-NRX的突触表达减少，但α-NRX没有。因此，我们的数据表明，AβOs与NRX相互作用，这种相互作用通过减少轴突β-NRX的表面表达来抑制NRX介导的突触前分化，从而为AβOs如何导致AD中的突触病理提供分子和机制见解。
Alzheimer’s disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD.