Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents.
Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents.
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DOI：
10.1016/j.neurobiolaging.2008.09.019
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发表时间：
2010-10
影响因子：
4.2
通讯作者：
Jin, Lee-Way
中科院分区：
文献类型：
--
作者：
Hong, Hyun-Seok;Maezawa, Izumi;Budamagunta, Madhu;Rana, Sandeep;Shi, Aibin;Vassar, Robert;Liu, Ruiwu;Lam, Kit S.;Cheng, R. Holland;Hua, Duy H.;Voss, John C.;Jin, Lee-Way
关键词：
阿尔茨海默病 (AD) 的特点是 β-淀粉样蛋白 (Aβ) 在大脑中以淀粉样蛋白的形式聚集沉积。为了促进通过放射性配体成像诊断 AD，已经开发了几种高度特异性的小分子淀粉样蛋白配体。由于淀粉样蛋白配体表现出优异的药代动力学特性和脑生物利用度，并且由于我们之前已经证明一些淀粉样蛋白配体以高亲和力结合高度神经毒性的Aβ寡聚物（AβO），因此它们也可能是抗Aβ疗法的有价值的候选者。在这里，我们从淀粉样蛋白配体库中鉴定出两种芴化合物，最初是基于它们阻止细胞内 AβO 继发的细胞死亡的能力。我们发现芴铅能够减少培养神经元和 5xFAD 小鼠中的淀粉样蛋白负担，包括 AβO 水平。为了解释这些体外和体内效应，我们发现铅芴会结合 AβO 并使其不稳定，如电子顺磁共振波谱研究所示，并阻止有害的 AβO-突触相互作用。因此，这些芴和未来的衍生物在 AD 治疗和研究中具有潜在用途。
Alzheimer’s disease (AD) is characterized by depositions of β-amyloid (Aβ) aggregates as amyloid in the brain. To facilitate diagnosis of AD by radioligand imaging, several highly specific small-molecule amyloid ligands have been developed. Because amyloid ligands display excellent pharmacokinetics properties and brain bioavailability, and because we have previously shown that some amyloid ligands bind the highly neurotoxic Aβ oligomers (AβO) with high affinities, they may also be valuable candidates for anti-Aβ therapies. Here we identified two fluorene compounds from libraries of amyloid ligands, initially based on their ability to block cell death secondary to intracellular AβO. We found that the lead fluorenes were able to reduce the amyloid burden including the levels of AβO in cultured neurons and in 5xFAD mice. To explain these in vitro and in vivo effects, we found that the lead fluorenes bind and destabilize AβO as shown by electron paramagnetic resonance spectroscopy studies, and block the harmful AβO-synapse interaction. These fluorenes and future derivatives, therefore, have a potential use in AD therapy and research.
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影响因子：
2.9
作者：
Kung, MP;Hou, C;Kung, HF
通讯作者：
Kung, HF
影响因子：
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作者：
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