Oligomers of amyloid-β (AβO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer’s disease (AD). However, the heterogeneous and dynamic nature of AβO and inadequate markers for AβO subtypes have stymied effective AβO identification and therapeutic targeting in vivo. We identified an AβO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine–asparagine–lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AβO^cSNK recognizes ∼50–60 kDa SDS-resistant soluble Aβ assemblages in AD brain and prolongs the lag phase of Aβ aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AβO^cSNK in two AD mouse models reduced soluble brain Aβ aggregates by 20–30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AβO^cSNK IgG1 response without epitope spreading to Aβ monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AβO^cSNK participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.

中文翻译：

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合理的结构化抗原决定基定义了有毒淀粉样β低聚物的不同亚类。

淀粉样蛋白-β（AβO）的低聚物被认为是阿尔茨海默氏病（AD）的突触毒性和淀粉样蛋白植入的关键。然而，AβO的异质性和动态性质以及AβO亚型的标记不足，已阻碍了有效的AβO鉴定和体内治疗靶向。我们在丝氨酸-天冬酰胺-赖氨酸（cSNK）的受限环中确定了赖氨酸28侧链的溶剂定向不同所定义的AβO亚类抗原决定簇，该现象很少在单体和原纤维集成体的分子动力学模拟中显示。靶向AβO的小鼠单克隆抗体^cSNK识别在AD脑中和延长~50-60 kDa的SDS-耐可溶性Aβ组合Aβ聚集的滞后期体外。小鼠IgG1抗AβO的急性外周输注两种AD小鼠模型中的^cSNK可使可溶性脑Aβ聚集物减少20–30％。长期对APP / PS1小鼠进行cSNK肽免疫可产生抗^AβOcSNK IgG1反应，而抗原表位不会扩散至Aβ单体或原纤维，并伴有整体PSD95表达的保留和改善的恐惧记忆。我们的数据表明，低聚型AβOcSNK在体内外^均参与突触毒性和Aβ聚集的传播。