A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease.
A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease.
复制标题
阿尔茨海默病中β-淀粉样蛋白原纤维毒性增强的可能机制
DOI：
10.1073/pnas.2309389120
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发表时间：
2023-09-05
影响因子：
11.1
通讯作者：
Strickland, Sidney
中科院分区：
文献类型：
--
作者：
Chen, Zu-Lin;Singh, Pradeep K.;Calvano, Marissa;Norris, Erin H.;Strickland, Sidney
淀粉样蛋白β肽（a β）是阿尔茨海默病（AD）的驱动因子。Aβ单体可以聚集并形成较大的可溶（低聚物/原纤维）和不可溶（原纤维）形式。有证据表明Aβ原原纤维是毒性最大的形式，但原因尚不清楚。与这种形式的a β在AD中的关键作用一致，最近fda批准了一种针对原纤维的治疗性抗体lecanemab，可以减缓AD患者的进展。血浆接触系统可以促进凝血和炎症，与AD的发病有关。该系统被Aβ激活，这可能导致与AD相关的血管和炎症病理。我们在这里表明，接触系统优先被Aβ原纤维激活。Aβ原纤维与凝血因子XII和高分子量激肽原结合，加速系统的激活。此外，lecanemab阻断了Aβ原纤维的接触系统激活。这项工作提供了AD中a β原纤维毒性的可能机制，以及lecanemab治疗有效的原因。
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.
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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：
20.3
作者：
Chen, Zu-Lin;Revenko, Alexey S.;Strickland, Sidney
通讯作者：
Strickland, Sidney
影响因子：
25
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
通讯作者：
Lannfelt, L
影响因子：
15.9
作者：
THOMPSON, RE;MANDLE, R;KAPLAN, AP
通讯作者：
KAPLAN, AP
影响因子：
11.2
作者：
Lee S;Viqar F;Zimmerman ME;Narkhede A;Tosto G;Benzinger TL;Marcus DS;Fagan AM;Goate A;Fox NC;Cairns NJ;Holtzman DM;Buckles V;Ghetti B;McDade E;Martins RN;Saykin AJ;Masters CL;Ringman JM;Ryan NS;Förster S;Laske C;Schofield PR;Sperling RA;Salloway S;Correia S;Jack C Jr;Weiner M;Bateman RJ;Morris JC;Mayeux R;Brickman AM;Dominantly Inherited Alzheimer Network
通讯作者：
Dominantly Inherited Alzheimer Network