Keto form of curcumin derivatives strongly binds to Aβ oligomers but not fibrils
Keto form of curcumin derivatives strongly binds to Aβ oligomers but not fibrils
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DOI：
10.1016/j.biomaterials.2021.120686
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发表时间：
2021-02-01
期刊：
影响因子：
14
通讯作者：
Tooyama, Ikuo
中科院分区：
文献类型：
--
作者：
Yanagisawa, Daijiro;Kato, Tomoko;Tooyama, Ikuo
β-淀粉样蛋白（A β）聚集体在脑中的积累发生在阿尔茨海默病（AD）进展的早期，非纤维状可溶性A β寡聚体特别具有神经毒性。在与A β原纤维结合的过程中，可以在其酮和烯醇互变异构体之间的平衡状态下存在的姜黄素主要以烯醇形式存在，并且酮形式与A β原纤维的结合活性弱得多。在这里，我们描述了姜黄素衍生物Shiga-Y51的酮形式对A β寡聚体显示出的强结合活性和其对A β原纤维的弱亲和力。此外，通过成像质谱，我们揭示了在AD小鼠模型中，Shiga-Y51的血脑屏障通透性及其在大脑皮层和海马中的积累，其中A β寡聚体主要位于海马中。姜黄素衍生物如Shiga-Y51的酮形式可能是有希望的种子化合物，用于开发靶向脑中A β寡聚体的成像探针和治疗剂。
The accumulation of beta-amyloid (A beta) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble A beta oligomers are particularly neurotoxic. During binding to A beta fibrils, curcumin, which can exist in an equilibrium state between its keto and enol tautomers, exists predominantly in the enol form, and binding activity of the keto form to A beta fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for A beta oligomers and its scant affinity for A beta fibrils. Furthermore, with imaging mass spectrometry we revealed the blood-brain barrier permeability of Shiga-Y51 and its accumulation in the cerebral cortex and the hippocampus, where A beta oligomers were mainly localized, in a mouse model of AD. The keto form of curcumin derivatives like Shiga-Y51 could be promising seed compounds to develop imaging probes and therapeutic agents targeting A beta oligomers in the brain.