Structural Biology & Bio-Informatics Division, CSIR - Indian Institute of Chemical Biology, Kolkata 700032, India.
ACS Chem Neurosci. 2021 Nov 3;12(21):4144-4152. doi: 10.1021/acschemneuro.1c00519. Epub 2021 Oct 20.
Cerebrovascular dysfunction is a common phenomenon in Alzheimer's patients, where fibrinogen is a major player. With the blood-brain barrier compromised, fibrinogen gains access to the brain, where its interaction with Aβ results in plasmin-resistant abnormal blood clots that are deposited in the cerebral blood vessels, a condition commonly encountered in Alzheimer's disease (AD) patients called cerebral amyloid angiopathy (CAA). So far, there have been no effective therapeutics available to combat AD-associated CAA. This study reports a 13-amino acid peptide (Pα-NPGRPEPGSAGTW) as a potential inhibitor of the fibrin-Aβ interaction along with the property to dissolve pre-existing plasmin-resistant abnormal clots. Strikingly, the identified sequence was found to be partially similar to a fragment of the fibrinogen α-chain reported to bind Aβ, the plasmin-resistant fibrinogen fragment (PRFF). Mechanistically, Pα interacts with Aβ in place of fibrinogen, thus inhibiting the toxic fibrin-Aβ interaction. However, it does not interfere with normal fibrin polymerization.
脑血管功能障碍是阿尔茨海默病患者的常见现象，纤维蛋白原是其中的主要参与者。由于血脑屏障受损，纤维蛋白原进入大脑，与 Aβ相互作用导致纤维蛋白稳定的异常血栓沉积在脑血管中，这种情况在阿尔茨海默病（AD）患者中很常见，被称为脑淀粉样血管病（CAA）。到目前为止，还没有有效的治疗方法来对抗 AD 相关的 CAA。本研究报告了一种 13 个氨基酸肽（Pα-NPGRPEPGSAGTW）作为纤维蛋白-Aβ相互作用的潜在抑制剂，同时具有溶解已存在的纤维蛋白稳定的异常血栓的特性。值得注意的是，所鉴定的序列与先前报道的与 Aβ结合的纤维蛋白原α链片段（PRFF）有部分相似，该片段是纤维蛋白原的一种纤维蛋白稳定的异常片段。从机制上讲，Pα与 Aβ相互作用取代了纤维蛋白原，从而抑制了毒性纤维蛋白-Aβ相互作用。然而，它并不干扰正常的纤维蛋白聚合。
