Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.
Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.
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DOI：
10.1002/chem.201601763
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发表时间：
2016-08-16
影响因子：
4.3
通讯作者：
Raskatov, Jevgenij A.
中科院分区：
文献类型：
--
作者：
Warner, Christopher J. A.;Dutta, Subrata;Foley, Alejandro R.;Raskatov, Jevgenij A.
淀粉样β肽42（Aβ42）是一种易聚集的肽，在阿尔茨海默病中起着关键作用。 我们报告说，通过谷氨酸22处的单一手性变化对肽的细微扰动导致肽的β折叠采用明显延迟。 这伴随着肽形成原纤维的倾向减弱，这与细胞结构水平的变化相关。引人注目的是，发现d-谷氨酸的掺入稳定了可溶性有序大分子组装体，增强了对PC 12细胞的细胞毒性，突出了晚期前驱Aβ聚集体在神经毒性中的重要性。
The amyloid beta peptide 42 (Aβ42) is an aggregation‐prone peptide that plays a pivotal role in Alzheimer′s disease. We report that a subtle perturbation to the peptide through a single chirality change at glutamate 22 leads to a pronounced delay in the β‐sheet adoption of the peptide. This was accompanied by an attenuated propensity of the peptide to form fibrils, which was correlated with changes at the level of the fibrillary architecture. Strikingly, the incorporation of d‐glutamate was found to stabilize a soluble, ordered macromolecular assembly with enhanced cytotoxicity to PC12 cells, highlighting the importance of advanced prefibrillary Aβ aggregates in neurotoxicity.
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作者：
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