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Toxic effects of endoplasmic reticulum stress transducer BBF2H7-derived small peptide fragments on neuronal cells
Brain Research ( IF 2.7 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.brainres.2020.147139
Koji Matsuhisa 1 , Longjie Cai 2 , Atsushi Saito 1 , Fumika Sakaue 3 , Yasunao Kamikawa 3 , Sachiko Fujiwara 3 , Rie Asada 4 , Yukitsuka Kudo 5 , Kazunori Imaizumi 2
Affiliation  

Aggregation, fibril formation, and deposition of amyloid β (Aβ) protein are believed to be the central pathogeneses of Alzheimer’s disease (AD). Numerous studies have shown that fibril formation is promoted by preformed seeds at the beginning of the aggregation process. Therefore, aggregated molecules that promote fibrillization of Aβ protein as seeds could affect the pathology. We recently found that approximately 40 amino acid hydrophobic peptides, BBF2H7-derived small peptide (BSP) fragments, are generated via intramembranous cleavage under endoplasmic reticulum (ER) stress conditions. Interestingly, similar to Aβ protein, the fragments exhibit a high aggregation propensity and form fibril structures. It has been noted that ER stress is involved in the pathogenesis of AD. In this study, we examined the effect of BSP fragments on aggregation and cytotoxicity of Aβ1–40 protein, which is generated as a major species of Aβ protein, but has a lower aggregative property than Aβ1–42 protein. We demonstrated that BSP fragments promote aggregation of Aβ1–40 protein. Aggregates of Aβ1–40 protein mediated by BSP fragments also exhibited potent neurotoxicity. Our findings suggest the possibility that BSP fragments affect accumulation of Aβ proteins and are involved in the pathogenesis of AD.



中文翻译:

内质网应激传感器BBF2H7衍生的小肽片段对神经元细胞的毒性作用

淀粉样蛋白 β (Aβ) 蛋白的聚集、原纤维形成和沉积被认为是阿尔茨海默病 (AD) 的核心病原体。许多研究表明,在聚集过程开始时,预制种子促进了原纤维的形成。因此,促进 Aβ 蛋白原纤维化作为种子的聚集分子可能会影响病理。我们最近发现大约 40 个氨基酸的疏水性肽、BBF2H7 衍生的小肽 (BSP) 片段是在内质网 (ER) 应激条件下通过膜内裂解产生的。有趣的是,与 Aβ 蛋白相似,这些片段表现出高聚集倾向并形成原纤维结构。已经注意到内质网应激参与 AD 的发病机制。在这项研究中,1-40蛋白,作为 Aβ 蛋白的主要种类产生,但与 Aβ 1-42蛋白相比具有较低的聚集特性。我们证明 BSP 片段促进 Aβ 1-40蛋白的聚集。由 BSP 片段介导的 Aβ 1-40蛋白聚集体也表现出强大的神经毒性。我们的研究结果表明 BSP 片段可能影响 Aβ 蛋白的积累并参与 AD 的发病机制。

更新日期:2020-10-06
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