Department of Medicine, Djavad Mowafaghian Centre for Brain Health , University of British Columbia , 2211 Wesbrook Mall , Vancouver , BC V6T 2B5 , Canada.
Department of Physics and Astronomy, Genome Sciences and Technology Program, Bioinformatics, Institute for Applied Math , University of British Columbia , Room 311, 6356 Agricultural Road , Vancouver , BC V6T 1Z2 , Canada.
ACS Chem Neurosci. 2018 Jul 18;9(7):1591-1606. doi: 10.1021/acschemneuro.7b00469. Epub 2018 Apr 16.
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 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 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 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 participates in synaptotoxicity and propagation of Aβ aggregation in vitro and in vivo.
淀粉样蛋白-β（AβO）寡聚体被认为是突触毒性和阿尔茨海默病（AD）淀粉样蛋白播种的关键。然而，AβO 的异质性和动态性质以及 AβO 亚型的充分标志物阻碍了体内有效的 AβO 识别和治疗靶向。我们确定了一个由赖氨酸 28 侧链在丝氨酸-天冬酰胺-赖氨酸（cSNK）的约束环中的不同溶剂取向定义的 AβO 亚类表位，在单体和纤维束的分子动力学模拟中很少显示。一种针对 AβO 的小鼠单克隆抗体识别 AD 脑中约 50-60 kDa SDS 抗性可溶性 Aβ 聚集物，并延长体外 Aβ 聚集的滞后期。在两种 AD 小鼠模型中，急性外周输注抗 AβO 的鼠 IgG1 可减少可溶性脑 Aβ 聚集物 20-30%。APP/PS1 小鼠的慢性 cSNK 肽免疫产生抗 AβO IgG1 反应，而不会导致表位扩展到 Aβ 单体或纤维，并且伴随着 PSD95 表达的全局保存和改善的线索恐惧记忆。我们的数据表明，寡聚体亚型 AβO 参与体外和体内的突触毒性和 Aβ 聚集的传播。
