Interactions between BIM Protein and Beta-Amyloid May Reveal a Crucial Missing Link between Alzheimer's Disease and Neuronal Cell Death
Interactions between BIM Protein and Beta-Amyloid May Reveal a Crucial Missing Link between Alzheimer's Disease and Neuronal Cell Death
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DOI：
10.1021/acschemneuro.9b00177
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Jelinek, Raz
中科院分区：
文献类型：
--
作者：
Malishev, Ravit;Nandi, Sukhendu;Jelinek, Raz
广泛的神经元细胞死亡是阿尔茨海默病的病理特征之一。虽然神经元死亡与包含 β-淀粉样蛋白 (Aβ) 肽的斑块的形成同时发生，但 Aβ（或其他阿尔茨海默病相关蛋白）与细胞毒性之间的直接因果关系尚未被发现。在这里，我们发现 BIM-BH3 是 BIM 的主要促凋亡结构域，是各种细胞凋亡级联中的关键蛋白，在阿尔茨海默病患者的脑细胞中发现其水平升高，与 42 残基淀粉样蛋白亚型 A beta 42 相互作用。值得注意的是，BIM-BH3 调节结构、纤维颤动途径、聚集形态和膜 A beta 42 的相互作用。特别是，BIM-BH3 抑制 A beta 42 原纤维形成，同时增强原原纤维组装。此外，我们发现 BIM-BH3/A beta 42 相互作用诱导人神经母细胞瘤细胞模型中的细胞死亡。总体而言，我们的数据提供了阿尔茨海默病患者神经细胞死亡以及 BIM 和 A beta 42 参与神经毒性过程的关键机制联系。
Extensive neuronal cell death is among the pathological hallmarks of Alzheimer's disease. While neuron death is coincident with formation of plaques comprising the beta-amyloid (A beta) peptide, a direct causative link between A beta (or other Alzheimer's-associated proteins) and cell toxicity is yet to be found. Here we show that BIM-BH3, the primary proapoptotic domain of BIM, a key protein in varied apoptotic cascades of which elevated levels have been found in brain cells of patients afflicted with Alzheimer's disease, interacts with the 42-residue amyloid isoform A beta 42. Remarkably, BIM-BH3 modulated the structure, fibrillation pathway, aggregate morphology, and membrane interactions of A beta 42. In particular, BIM-BH3 inhibited A beta 42 fibril-formation, while it simultaneously enhanced protofibril assembly. Furthermore, we discovered that BIM-BH3/A beta 42 interactions induced cell death in a human neuroblastoma cell model. Overall, our data provide a crucial mechanistic link accounting for neuronal cell death in Alzheimer's disease patients and the participation of both BIM and A beta 42 in the neurotoxicity process.