Systematic and standardized comparison of reported amyloid- receptors for sufficiency, affinity, and Alzheimer's disease relevance
Systematic and standardized comparison of reported amyloid- receptors for sufficiency, affinity, and Alzheimer's disease relevance
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DOI：
10.1074/jbc.ra118.006252
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发表时间：
2019-04-12
影响因子：
4.8
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
--
作者：
Smith, Levi M.;Kostylev, Mikhail A.;Strittmatter, Stephen M.
阿尔茨海默病（AD）患者脑中淀粉样蛋白（A）肽（Ao）的寡聚体组装对神经元突触有毒性。已经提出了十几种A受体候选物负责AD小鼠模型中分子病理学和记忆障碍的各个方面。以前的研究中缺乏一致的实验设计不同的受体候选人限制了这些候选人的相对作用的评价，在该领域内产生了一些争议。在这里，使用基于细胞的测定与几个A物种，包括Ao从AD脑尸检获得，我们直接比较了A-结合能力的多种受体候选人，同时占表达的变化和确认细胞表面表达。在对15种已报道的A受体的调查中，只有细胞朊病毒蛋白（PrPC）、Nogo受体1（NgR 1）和白细胞免疫球蛋白样受体亚家族B成员2（LilrB 2）表现出与合成A的突触毒性组装体直接结合。PrPC和NgR 1优先结合突触毒性寡聚体，而不是无毒单体，寡聚体制备方法没有显着改变我们的结合结果。缺乏NgR 1和LilrB 2的海马神经元表现出部分Ao结合减少，但这种减少低于在相同条件下缺乏PrPC的神经元。最后，结合研究与可溶性Ao从人类AD大脑揭示了强亲和力的PrPC，弱亲和力的NgR 1，和没有检测到的亲和力LilrB 2。这些研究结果澄清了先前报道的A受体在受控条件下的相对贡献，并突出了PrPC作为A结合位点的重要性。
Oligomeric assemblies of amyloid- (A) peptide (Ao) in the brains of individuals with Alzheimer's disease (AD) are toxic to neuronal synapses. More than a dozen A receptor candidates have been suggested to be responsible for various aspects of the molecular pathology and memory impairment in mouse models of AD. A lack of consistent experimental design among previous studies of different receptor candidates limits evaluation of the relative roles of these candidates, producing some controversy within the field. Here, using cell-based assays with several A species, including Ao from AD brains obtained by autopsy, we directly compared the A-binding capacity of multiple receptor candidates while accounting for variation in expression and confirming cell surface expression. In a survey of 15 reported A receptors, only cellular prion protein (PrPC), Nogo receptor 1 (NgR1), and leukocyte immunoglobulin-like receptor subfamily B member 2 (LilrB2) exhibited direct binding to synaptotoxic assemblies of synthetic A. Both PrPC and NgR1 preferentially bound synaptotoxic oligomers rather than nontoxic monomers, and the method of oligomer preparation did not significantly alter our binding results. Hippocampal neurons lacking both NgR1 and LilrB2 exhibited a partial reduction of Ao binding, but this reduction was lower than in neurons lacking PrPC under the same conditions. Finally, binding studies with soluble Ao from human AD brains revealed a strong affinity for PrPC, weak affinity for NgR1, and no detectable affinity for LilrB2. These findings clarify the relative contributions of previously reported A receptors under controlled conditions and highlight the prominence of PrPC as an A-binding site.