Anti-HK antibody reveals critical roles of a 20-residue HK region for Aβ-induced plasma contact system activation.
Anti-HK antibody reveals critical roles of a 20-residue HK region for Aβ-induced plasma contact system activation.
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DOI：
10.1182/bloodadvances.2021006612
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发表时间：
2022-05-24
期刊：
影响因子：
7.5
通讯作者：
Norris, Erin H.
中科院分区：
文献类型：
--
作者：
Chen, Zu-Lin;Singh, Pradeep Kumar;Horn, Katharina;Strickland, Sidney;Norris, Erin H.
HK结构域6中的20个残基区域在Aβ42诱导的接触系统激活中起关键作用。3E 8阻断PK和FXI与HK的结合，分解HK/PK和HK/FXI复合物，并延迟内源性凝血。阿尔茨海默病（AD）是一种神经退行性疾病，是痴呆的主要原因。血管异常和神经炎症在AD发病机制中起作用。导致纤维蛋白凝块形成和缓激肽释放的血浆接触活化在许多AD患者中升高，可能是由于AD的致病肽β-淀粉样蛋白（Aβ）诱导其活化的能力。由于该系统的过度激活可能对AD患者有害，因此开发抑制剂可能是有益的。在这里，我们发现3E 8，一种针对高分子量激肽原（HK）结构域6中20个氨基酸区域的抗体，抑制Aβ诱导的内源性凝血。在机制上，3E 8通过阻断前激肽释放酶（PK）和因子XI（FXI）与HK的结合来抑制接触系统活化，从而防止它们的活化和因子XII（FXII）的持续活化。由于其对HK的强结合亲和力，3E 8抗体还可以在不存在接触系统激活剂的情况下分解正常人血浆中的HK/PK和HK/FXI复合物，表明其预防能力。此外，Aβ与FXII和HK两者的结合对于Aβ介导的接触系统活化是关键的。这些结果表明HK结构域6中的20个氨基酸区域在Aβ诱导的接触系统激活中起关键作用，并且该区域可能提供抑制或预防相关疾病中接触系统激活的有效策略。
A 20-residue region in domain 6 of HK plays a critical role in Aβ42-induced contact system activation. 3E8 blocks PK and FXI binding to HK, disassembles HK/PK and HK/FXI complexes, and delays intrinsic coagulation. Alzheimer’s disease (AD) is a neurodegenerative disorder and the leading cause of dementia. Vascular abnormalities and neuroinflammation play roles in AD pathogenesis. Plasma contact activation, which leads to fibrin clot formation and bradykinin release, is elevated in many AD patients, likely due to the ability of AD’s pathogenic peptide β-amyloid (Aβ) to induce its activation. Since overactivation of this system may be deleterious to AD patients, the development of inhibitors could be beneficial. Here, we show that 3E8, an antibody against a 20-amino acid region in domain 6 of high molecular weight kininogen (HK), inhibits Aβ-induced intrinsic coagulation. Mechanistically, 3E8 inhibits contact system activation by blocking the binding of prekallikrein (PK) and factor XI (FXI) to HK, thereby preventing their activation and the continued activation of factor XII (FXII). The 3E8 antibody can also disassemble HK/PK and HK/FXI complexes in normal human plasma in the absence of a contact system activator due to its strong binding affinity for HK, indicating its prophylactic ability. Furthermore, the binding of Aβ to both FXII and HK is critical for Aβ-mediated contact system activation. These results suggest that a 20-amino acid region in domain 6 of HK plays a critical role in Aβ-induced contact system activation, and this region may provide an effective strategy to inhibit or prevent contact system activation in related disorders.
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影响因子：
16.2
作者：
Cortes-Canteli, Marta;Paul, Justin;Norris, Erin H.;Bronstein, Robert;Ahn, Hyung Jin;Zamolodchikov, Daria;Bhuvanendran, Shivaprasad;Fenz, Katherine M.;Strickland, Sidney
通讯作者：
Strickland, Sidney
影响因子：
16.6
作者：
Iturria-Medina Y;Sotero RC;Toussaint PJ;Mateos-Pérez JM;Evans AC;Alzheimer’s Disease Neuroimaging Initiative
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
影响因子：
4.2
作者：
Ashby, Emma L.;Love, Seth;Kehoe, Patrick G.
通讯作者：
Kehoe, Patrick G.
影响因子：
15.9
作者：
Flick, Matthew J.;LaJeunesse, Christine M.;Degen, Jay L.
通讯作者：
Degen, Jay L.
影响因子：
20.3
作者：
Chen, Zu-Lin;Revenko, Alexey S.;Strickland, Sidney
通讯作者：
Strickland, Sidney