Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing
Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing
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DOI：
10.1038/s41467-019-09164-3
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发表时间：
2019-03-22
影响因子：
16.6
通讯作者：
Bettler, Bernhard
中科院分区：
文献类型：
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作者：
Dinamarca, Margarita C.;Raveh, Adi;Bettler, Bernhard
GABA（B）受体（GBR）是突触释放的关键调节因子，但对控制其突触前丰度的运输机制知之甚少。我们现在表明，APP，AJAP-1和PIANP中的序列相关表位以纳摩尔亲和力与突触前GBR的N-末端sushi结构域结合。在这三种相互作用的蛋白质中，APP的遗传缺失选择性地损害GBR介导的突触前抑制和轴突GBR表达。蛋白质组学和功能分析表明，APP与JIP和钙结合蛋白，连接APP/GBR复合物的货物囊泡的轴突运输马达。与GBR的复合物形成稳定了细胞表面的APP，并减少了APP蛋白水解为A β，A β是阿尔茨海默病患者老年斑的一种成分。因此，APP/GBR复合物的形成将突触前GBR运输与A β形成联系起来。我们的研究结果支持阿尔茨海默病中功能失调的轴突运输和GBR表达减少增加A β形成。
GABA(B) receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to A beta, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to A beta formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases A beta formation.