Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo.
Inhibition of Alzheimer's amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo.
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DOI：
10.1111/j.1471-4159.2008.05866.x
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发表时间：
2009-02
影响因子：
4.7
通讯作者：
Hua DH
中科院分区：
文献类型：
--
作者：
Hong HS;Rana S;Barrigan L;Shi A;Zhang Y;Zhou F;Jin LW;Hua DH
小的淀粉样蛋白β1-42聚集体对神经元具有毒性，可能是阿尔茨海默病(AD)的主要毒性物种。降低Aβ水平、防止Aβ聚集、消除现有Aβ聚集的方法已被提出用于AD的治疗。一种名为CP2的三环吡喃酮被发现可以防止与Aβ寡聚体相关的细胞死亡。我们研究了CP2可能的神经保护机制。表面等离子体共振谱显示CP2与Aβ42低聚物直接结合。圆二色谱表明，Cp2存在48h后，单体Aβ42多肽仍呈无规卷曲/α螺旋结构。原子力显微镜研究表明，Cp2具有与刚果红和姜黄素相似的抑制Aβ42聚集的能力。原子力显微镜封闭流体细胞研究表明，CP2解聚了Aβ42低聚体和原纤维。Cp2还使用蛋白质定量方法阻止Aβ纤颤。用Cp2治疗5x FAD小鼠(一种产生Aβ42的强大AD动物模型)，两周疗程后，非纤维性和纤维性Aβ的种类分别减少了40%和50%。我们的结果提示，CP2可能通过阻止Aβ聚集和解聚现有的Aβ寡聚体和原纤维而有益于AD患者。
Small amyloid β 1–42 aggregates are toxic to neurons and may be the primary toxic species in Alzheimer’s disease (AD). Methods to reduce the level of Aβ, prevent Aβ aggregation, and eliminate existing Aβ aggregates have been proposed for treatment of AD. A tricyclic pyrone named CP2 is found to prevent cell death associated with Aβ oligomers. We studied the possible mechanisms of neuroprotection by CP2. Surface plasmon resonance spectroscopy shows a direct binding of CP2 with Aβ42 oligomer. Circular dichroism spectroscopy reveals monomeric Aβ42 peptide remains as a random coil/α-helix structure in the presence of CP2 over 48 h. Atomic force microscopy (AFM) studies show CP2 exhibits similar ability to inhibit Aβ42 aggregation as that of Congo Red and curcumin. AFM closed-fluid cell study demonstrates that CP2 disaggregates Aβ42 oligomers and protofibrils. CP2 also blocks Aβ fibrillations using a protein quantification method. Treatment of 5x FAD mice, a robust Aβ42-producing animal model of AD, with a two-week course of CP2 resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species, respectively. Our results suggest that CP2 might be beneficial to AD patients by preventing Aβ aggregation and disaggregating existing Aβ oligomers and protofibrils.
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影响因子：
4.2
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
通讯作者：
Jin, Lee-Way
DOI：
10.1073/pnas.0405941101
发表时间：
2004-10-05
影响因子：
11.1
作者：
Blanchard, BJ;Chen, A;Ingram, VM
通讯作者：
Ingram, VM
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
影响因子：
2.9
作者：
Chromy, BA;Nowak, RJ;Klein, WL
通讯作者：
Klein, WL