NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease
NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease
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DOI：
10.15252/emmm.201809695
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发表时间：
2019-04-01
影响因子：
11.1
通讯作者：
Lichtenthaler, Stefan F.
中科院分区：
文献类型：
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作者：
Brummer, Tobias;Mueller, Stephan A.;Lichtenthaler, Stefan F.
金属蛋白酶ADAM 10是阿尔茨海默病的药物靶点，它切割淀粉样前体蛋白（APP）并降低淀粉样β蛋白。然而，ADAM10具有额外的底物，这可能会在治疗性ADAM10激活后引起基于机制的副作用。然而，除了APP之外，它们还可以作为生物标志物来监测患者中的ADAM10活性并开发APP选择性ADAM10激活剂。我们的研究表明，这样的底物之一是神经细胞粘附蛋白NrCAM。ADAM10在体外以NrCAM依赖的方式控制NrCAM表面水平和调节神经突生长。然而，与APP相反，NrCAM的ADAM10裂解不受ADAM10激活剂阿维A的刺激，这表明底物选择性ADAM10激活可能是可行的。事实上，来自II期临床试验的人CSF的全蛋白质组分析表明，阿维A增强了由ADAM 10切割的APP，从而避免了大脑中的大多数其他ADAM 10底物，包括NrCAM。总之，这项研究证明了神经突起生长中ADAM 10的NrCAM依赖性功能，并揭示了底物选择性，治疗性ADAM 10激活是可能的，可以用NrCAM进行监测。
The metalloprotease ADAM10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein (APP) and lowers amyloid-beta. Yet, ADAM10 has additional substrates, which may cause mechanism-based side effects upon therapeutic ADAM10 activation. However, they may also serve-in addition to APP-as biomarkers to monitor ADAM10 activity in patients and to develop APP-selective ADAM10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein NrCAM. ADAM10 controlled NrCAM surface levels and regulated neurite outgrowth in vitro in an NrCAM-dependent manner. However, ADAM10 cleavage of NrCAM, in contrast to APP, was not stimulated by the ADAM10 activator acitretin, suggesting that substrate-selective ADAM10 activation may be feasible. Indeed, a whole proteome analysis of human CSF from a phase II clinical trial showed that acitretin, which enhanced APP cleavage by ADAM10, spared most other ADAM10 substrates in brain, including NrCAM. Taken together, this study demonstrates an NrCAM-dependent function for ADAM10 in neurite outgrowth and reveals that a substrate-selective, therapeutic ADAM10 activation is possible and may be monitored with NrCAM.