Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, 520-2192, Japan.
Industrial Research Center of Shiga Prefecture, 232 Kamitoyama, Ritto, 520-3004, Japan.
Biomaterials. 2021 Mar;270:120686. doi: 10.1016/j.biomaterials.2021.120686. Epub 2021 Jan 23.
The accumulation of β-amyloid (Aβ) aggregates in the brain occurs early in the progression of Alzheimer's disease (AD), and non-fibrillar soluble Aβ oligomers are particularly neurotoxic. During binding to Aβ 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 Aβ fibrils is much weaker. Here we described the strong binding activity the keto form of curcumin derivative Shiga-Y51 shows for Aβ oligomers and its scant affinity for Aβ 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 Aβ 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 Aβ oligomers in the brain.
β-淀粉样蛋白 (Aβ) 聚集物在阿尔茨海默病 (AD) 的进展早期在大脑中积累，而非纤维状可溶性 Aβ 寡聚物具有特别的神经毒性。在与 Aβ 原纤维结合时，姜黄素可以在其酮式和烯醇式互变异构体之间达到平衡状态，主要以烯醇形式存在，而酮式对 Aβ 原纤维的结合活性要弱得多。在这里，我们描述了姜黄素衍生物 Shiga-Y51 的酮式对 Aβ 寡聚物具有很强的结合活性，而对 Aβ 原纤维的亲和力则很小。此外，通过成像质谱，我们揭示了 Shiga-Y51 在 AD 小鼠模型中的血脑屏障通透性及其在大脑皮层和海马中的积累，Aβ 寡聚物主要定位于这些区域。像 Shiga-Y51 这样的姜黄素衍生物的酮式可能是有前途的种子化合物，可以开发针对大脑中 Aβ 寡聚物的成像探针和治疗剂。
