Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2023 Sep 5;120(36):e2309389120. doi: 10.1073/pnas.2309389120. Epub 2023 Aug 28.
The amyloid-beta peptide (Aβ) is a driver of Alzheimer's disease (AD). Aβ monomers can aggregate and form larger soluble (oligomers/protofibrils) and insoluble (fibrils) forms. There is evidence that Aβ protofibrils are the most toxic form, but the reasons are not known. Consistent with a critical role for this form of Aβ in AD, a recently FDA-approved therapeutic antibody targeted against protofibrils, lecanemab, slows the progression of AD in patients. The plasma contact system, which can promote coagulation and inflammation, has been implicated in AD pathogenesis. This system is activated by Aβ which could lead to vascular and inflammatory pathologies associated with AD. We show here that the contact system is preferentially activated by protofibrils of Aβ. Aβ protofibrils bind to coagulation factor XII and high molecular weight kininogen and accelerate the activation of the system. Furthermore, lecanemab blocks Aβ protofibril activation of the contact system. This work provides a possible mechanism for Aβ protofibril toxicity in AD and why lecanemab is therapeutically effective.
淀粉样蛋白-β肽（Aβ）是阿尔茨海默病（AD）的驱动因素。Aβ单体可以聚集并形成更大的可溶性（寡聚体/原纤维）和不溶性（纤维）形式。有证据表明，Aβ原纤维是最具毒性的形式，但原因尚不清楚。最近，一种针对原纤维的经 FDA 批准的治疗性抗体——仑卡奈单抗，因其对 AD 患者的进展具有减缓作用，从而支持了这种形式的 Aβ 在 AD 中的关键作用。血浆接触系统可以促进凝血和炎症，与 AD 的发病机制有关。我们在这里表明，接触系统优先被 Aβ原纤维激活。Aβ原纤维结合凝血因子 XII 和高分子量激肽原，并加速系统的激活。此外，仑卡奈单抗阻止 Aβ原纤维激活接触系统。这项工作为 AD 中 Aβ原纤维毒性的可能机制以及仑卡奈单抗具有治疗效果的原因提供了依据。
